KAWASE Atsushi

Researcher Information

Degree

• Ph.D（2005/03 Kyoto University）

URL

https://www.phar.kindai.ac.jp/biopharm/

J-Global ID

• 201401039717743689

Research Interests

• transporter   肝障害   炎症   ERストレス   エクソソーム   

Research Areas

• Life sciences / Clinical pharmacy

Association Memberships

• THE JAPANESE SOCIETY OF TOXICOLOGY   日本プロテオーム学会   THE JAPANESE SOCIETY FOR THE STUDY OF XENOBIOTICS   THE PHARMACEUTICAL SOCIETY OF JAPAN   THE ACADEMY OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY, JAPAN   

Published Papers

• Distinct roles of HMGB1 in the regulation of P‑glycoprotein expression in the liver and kidney of mice with lipopolysaccharide‑induced inflammation.

  Atsushi Kawase; Kota Irie; Naoya Matsuda; Yuzuki Takai; Hiroaki Shimada; Masahiro Iwaki

  Molecular medicine reports 26 (5) 2022/11 

  The role of high mobility group box 1 (HMGB1) in the regulation of efflux transporters in the liver and kidney remains unclear, although it has been reported that HMGB1 can increase P‑glycoprotein (P‑gp) expression in the brain. The present study aimed to clarify the involvement of HMGB1 in the regulation of P‑gp expression in the liver and kidney of mice with lipopolysaccharide (LPS)‑induced inflammation. Mice were treated with LPS or LPS + glycyrrhizin (GL); GL is as an HMGB1 inhibitor. Subsequently, the expression levels of transporters, such as P‑gp, and HMGB1 receptors, such as toll‑like receptor (TLR)4 and receptor for advanced glycation end‑products (RAGE), were determined by quantitative PCR and LC‑MS/MS‑based targeted proteomics. For the in vitro study, HepG2 and KMRC‑1 cells were used, as was a co‑culture of KMRC‑1 and differentiated THP‑1 cells. The mRNA and protein expression levels of Mdr1a and Tlr4 in the kidneys of LPS + GL‑treated mice were significantly decreased compared with those in LPS mice. The results indicated that HMGB1 had little effect on the expression of Mdr1a and Tlr4 in the liver, since there was little change in of Mdr1a and Mdr1b expression between the LPS and LPS + GL‑treated mice. Notably, regarding MDR1 mRNA expression, KMRC‑1 cells were more responsive to LPS than HepG2 cells, and KMRC‑1 cells treated with LPS exhibited increased levels compared with control KMRC‑1 cells. In differentiated THP‑1 cells, LPS treatment decreased the mRNA expression levels of TLR4, whereas they were restored to control levels by HMGB1. In conclusion, HMGB1 in the plasma and TLR4 in macrophages may be involved in the regulation of P‑gp expression in the kidneys of inflamed mice.
• Species differences in liver microsomal hydrolysis of acyl glucuronide in humans and rats.

  Hiroyuki Ikuta; Hiroaki Shimada; Kenjiro Sakamoto; Rena Nakamura; Atsushi Kawase; Masahiro Iwaki

  Xenobiotica; the fate of foreign compounds in biological systems 52 (7) 1 - 28 2022/10 

  Acyl glucuronides (AGs) are known as one of the causes of idiosyncratic drug toxicity (IDT). Although AGs can be enzymatically hydrolysed by β-glucuronidase and esterase, much information on their characteristics and species differences is lacking. This study was aimed to clarify species differences in AG hydrolysis between human and rat liver microsomes (HLM and RLM).To evaluate the AG hydrolysis profile, and the contribution of β-glucuronidase and esterase towards AG hydrolysis in HLM and RLM, nonsteroidal anti-inflammatory drugs (NSAIDs) were used. AGs were incubated with 0.1 M Tris-HCl buffer (pH 7.4) and 0.3 mg/mL HLM or RLM in the absence or presence of β-glucuronidase inhibitor, D-saccharic acid 1,4-lactone (D-SL) and esterase inhibitor, phenylmethylsulfonyl fluoride (PMSF).AGs of zomepirac (ZOM-AG), mefenamic acid (MEF-AG), and etodolac (ETO-AG) showed significantly higher AG hydrolysis rates in RLM than in HLM. Esterases were found to serve as AG hydrolases dominantly in HLM, whereas both esterases and β-glucuronidase equally contribute to AG hydrolysis in RLM. However, MEF-AG and ETO-AG were hydrolysed only by β-glucuronidase.We demonstrated for the first time that the activity of AG hydrolases towards NSAID-AGs differs between humans and rats.
• Diclofenac-Induced Cytotoxicity in Direct and Indirect Co-Culture of HepG2 Cells with Differentiated THP-1 Cells.

  Atsushi Kawase; Ouka Takashima; Satsuki Tanaka; Hiroaki Shimada; Masahiro Iwaki

  International journal of molecular sciences 23 (15) 2022/08 

  Non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (DIC) frequently induce drug-induced liver injury (DILI). It is unclear whether macrophages such as M1 and M2 participate in NSAID-associated DILI; elucidating this relationship could lead to a better understanding of the detailed mechanism of DILI. We co-cultured human hepatoma HepG2 cells with M1 or M2 derived from human monocytic leukemia THP-1 cells to examine the roles of M1 and M2 in DIC-induced cytotoxicity. DIC was added to the direct or indirect co-cultures of HepG2 cells with M1 or M2 (HepG2/M1 or HepG2/M2, respectively) at cell ratios of (1:0, 1:0.1, 1:0.4, and 1:1). In both direct and indirect HepG2/M2 co-cultures (1:0.4), there was lower lactate dehydrogenase release compared with HepG2/M1 co-cultures. Other NSAIDs as well as DIC showed similar protective effects of DIC-induced cytotoxicity. There were only slight differences in mRNA levels of apoptosis- and endoplasmic reticulum stress-associated factors between M1 and M2 after DIC treatment, suggesting that other factors determined the protective effects of M2 on DIC-induced cytotoxicity. Levels of high mobility group box 1 (HMGB1) in the medium and the mRNA expression levels of HMGB1 receptors were different between M1 and M2 after DIC treatment. Increased HMGB1 concentrations and expression of toll-like receptor 2 mRNA in M1 were observed compared with M2 after DIC treatment. In conclusion, these results suggested that the HMGB1/TLR2 signaling axis can be suppressed in M2 but not M1, leading to the different roles of M1 and M2 in NSAID-induced cytotoxicity.
• Slc25a39 and Slc25a40 Expression in Mice with Bile Duct Ligation or Lipopolysaccharide Treatment.

  Atsushi Kawase; Momoko Hatanaka; Naoya Matsuda; Hiroaki Shimada; Masahiro Iwaki

  International journal of molecular sciences 23 (15) 2022/08 

  SLC25A39/40, involved in mitochondrial GSH (mGSH) import from the cytoplasm, is essential for protection against oxidative stress and mitochondrial dysfunction. We examined the effects of cholestasis, through bile duct ligation (BDL) and lipopolysaccharide (LPS)-induced inflammation in mice, on Slc25a39/40 expression. Additionally, we used human clear cell renal carcinoma (KMRC-1) cells to elucidate the mechanism of regulation of SLC25A39/40 expression in the kidneys after LPS treatment. BDL resulted in a decrease in Slc25a39 mRNA in the liver and a decrease in Slc25a39/40 mRNA and protein in the kidneys. Consequently, there was a significant decrease in mGSH levels in the kidneys of BDL mice compared with those in sham mice. LPS treatment resulted in increased Slc25a40 expression in the kidneys. In KMRC-1 cells, the combination treatment of LPS-RS or FPS-ZM1 with LPS suppressed the LPS-induced increase in SLC25A40, suggesting that SLC25A40 expression could be regulated by the signaling pathway via toll-like receptor 4 and the receptor for advanced glycation end products, respectively. Our findings contribute to understanding the role of mGSH in the maintenance of the mitochondrial redox state. To the best of our knowledge, this is the first study that demonstrates the changes in Slc25a39/40 expression in mice with cholestasis-associated renal injury and LPS-induced inflammation.
• Stereoselective Covalent Adduct Formation of Acyl Glucuronide Metabolite of Nonsteroidal Anti-Inflammatory Drugs with UDP-Glucuronosyltransferase.

  Atsushi Kawase; Rio Yamashita; Tsubasa Yoshizato; Mashiro Yoshikawa; Hiroaki Shimada; Masahiro Iwaki

  International journal of molecular sciences 23 (9) 2022/04 

  A reactive metabolite of nonsteroidal anti-inflammatory drugs (NSAIDs), acyl-β-D-glucuronide (AG), covalently binds to endogenous proteins. The covalent adduct formation of NSAIDs-AG may lead to the dysfunction of target proteins. Therefore, it is important to clarify the detailed characterization of the formation of covalent protein adducts of NSAID-AG. UDP-glucuronosyltransferase (UGT) catalyzes the conversion of NSAIDs to NSAIDs-AG. The aim of this study was to perform a quantitative analysis of the covalent adduct formation of NSAIDs-AG with UGT. Diclofenac-AG and ketoprofen-AG formed covalent adducts with organelle proteins. Next, the number of covalent adducts formed between NSAIDs-AG and UGT isoforms (UGT1A1, UGT1A9, UGT2B4, and UGT2B9) was determined. The capacity of diclofenac-AG to form covalent adducts with UGT1A9 or UGT2B7 was approximately 10 times higher than that of mefenamic acid-AG. The amounts of covalent adducts of AG of propionic acid derivative NSAIDs with UGT2B were higher than those with UGT1A. Stereoselectivity was observed upon covalent binding to UGT. A significant negative correlation between the half-lives of NSAIDs-AG in phosphate buffers and the amount of covalent adduct with UGT2B7 was observed, suggesting the more labile NSAID-AG forms higher irreversible bindings to UGT. This report provides comprehensive information on the covalent adduct formation of NSAIDs-AGs with UGT.
• Relationship between the risk of idiosyncratic drug toxicity and formation and degradation profiles of acyl-glucuronide metabolites of nonsteroidal anti-inflammatory drugs in rat liver microsomes

  Shimada H; Ikuta H; Kumazawa K; Nomi M; Shiojiri M; Kawase A; Iwaki M

  Eur J Pharm Sci 2022/04 [Refereed]
  
• Ilex latifolia葉抽出物の食後血糖上昇抑制作用

  笹井 剛一; 島田 紘明; 上野 省一; 川瀬 篤史; 森川 敏生; 岩城 正宏

  日本薬学会年会要旨集 (公社)日本薬学会 142年会 27T - pm06S 0918-9823 2022/03
• Ilex latifolia葉抽出物の食後血糖上昇抑制作用

  笹井 剛一; 島田 紘明; 上野 省一; 川瀬 篤史; 森川 敏生; 岩城 正宏

  日本薬学会年会要旨集 (公社)日本薬学会 142年会 27T - pm06S 0918-9823 2022/03
• Assessment of hepatic prostaglandin E2 level in carbamazepine induced liver injury.

  Ken-Ichi Oba; Hiroaki Shimada; Ryota Hashimoto; Atsushi Kawase; Takeo Nakanishi; Masahiro Iwaki

  Endocrine regulations 56 (1) 22 - 30 2022/02 

  Objective. Carbamazepine (CBZ), a widely used antiepileptic drug, is one major cause of the idiosyncratic liver injury along with immune reactions. Conversely, prostaglandin E2 (PGE2) demonstrates a hepatoprotective effect by regulating immune reactions and promoting liver repair in various types of liver injury. However, the amount of hepatic PGE2 during CBZ-induced liver injury remains elusive. In this study, we aimed to evaluate the hepatic PGE2 levels during CBZ-induced liver injury using a mouse model. Methods. Mice were orally administered with CBZ at a dose of 400 mg/kg for 4 days, and 800 mg/kg on the 5th day. Results. Plasma alanine transaminase (ALT) level increased in some of mice 24 h after the last CBZ administration. Although median value of hepatic PGE2 amount in the CBZ-treated mice showed same extent as vehicle-treated control mice, it exhibited significant elevated level in mice with severe liver injury presented by a plasma ALT level >1000 IU/L. According to these results, mice had a plasma ALT level >1000 IU/L were defined as responders and the others as non-responders in this study. Even though, the hepatic PGE2 levels increased in responders, the hepatic expression and enzyme activity related to PGE2 production were not upregulated when compared with vehicle-treated control mice. However, the hepatic 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression and activity decreased significantly in responders when compared with control mice. Conclusions. These results indicate that elevated hepatic PGE2 levels can be attributed to the downregulation of 15-PGDH expression under CBZ-induced liver injury.
• Discovery of Pimozide Derivatives as Novel T-type Calcium Channel Inhibitors with Little Binding Affinity to Dopamine D2 Receptors for Treatment of Somatic and Visceral Pain

  Yoshihito Kasanami; Chihiro Ishikawa; Takahiro Kino; Momoka Chonan; Naoki Toyooka; Yasuhiro Takashima; Yuriko Iba; Fumiko Sekiguchi; Maho Tsubota; Tsuyako Ohkubo; Shigeru Yoshida; Atsushi Kawase; Takuya Okada; Atsufumi Kawabata

  European Journal of Medicinal Chemistry 243 114716 - 114716 2022 [Refereed]
   

  T-type Ca2+ channels (T-channels), particularly Cav3.2 and Cav3.1 isoforms, are promising targets for treating various diseases including intractable pain. Given the potent inhibitory activity of pimozide, an antipsychotic, against T-channels, we conducted structure-activity relationship studies of pimozide derivatives, and identified several compounds including 3a, 3s, and 4 that had potency comparable to that of pimozide in inhibiting T-channels, but little binding affinity to dopamine D2 receptors. The introduction of a phenylbutyl group on the benzoimidazole nuclei of pimozide was considered a key structural modification to reduce the binding affinity to D2 receptors. Those pimozide derivatives potently suppressed T-channel-dependent somatic and visceral pain in mice, without causing any motor dysfunctions attributable to D2 receptor blockade, including catalepsy. The present study thus provides an avenue to develop novel selective T-channel inhibitors available for pain management via the structural modification of existing medicines.
• Protein Kinase N Family Negatively Regulation Constitutive Androstane Receptor-mediated Transcriptional Induction of Cytochrome P450 2b10 in the Livers of Mice

  Kawase A; Mukai H; Tateishi S; Kuroda S; Kazaoka A; Satoh R; Shimada H; Sugiura R; Iwaki M

  J Pharmacol Exp Ther 379 (1) 53 - 63 2021 [Refereed]
   

  In receptor-type transcription factors-mediated cytochrome P450 (P450) induction, few studies have attempted to clarify the roles of protein kinase N (PKN) in the transcriptional regulation of P450s. This study aimed to examine the involvement of PKN in the transcriptional regulation of P450s by receptor-type transcription factors, including the aryl hydrocarbon receptor, constitutive androstane receptor (CAR), and pregnane X receptor. The mRNA and protein levels and metabolic activity of P450s in the livers of wild-type (WT) and double-mutant (D) mice harboring both PKN1 kinase-negative knock-in and PKN3 knockout mutations [PKN1 T778A/T778A; PKN3 -/-] were determined after treatment with activators for receptor-type transcription factors. mRNA and protein levels and metabolic activity of CYP2B10 were significantly higher in D mice treated with the CAR activator phenobarbital (PB) but not with 1,4-bis((3,5-dichloropyridin-2-yl)oxy)benzene compared with WT mice. We examined the CAR-dependent pathway regulated by PKN after PB treatment because the extent of CYP2B10 induction in WT and D mice was notably different in response to treatment with different CAR activators. The mRNA levels of Cyp2b10 in primary hepatocytes from WT and D mice treated with PB alone or in combination with Src kinase inhibitor 1 (SKI-1) or U0126 (a mitogen-activated protein kinase inhibitor) were evaluated. Treatment of hepatocytes from D mice with the combination of PB with U0126 but not SKI-1 significantly increased the mRNA levels of Cyp2b10 compared with those from the corresponding WT mice. These findings suggest that PKN may have inhibitory effects on the Src-receptor for activated C kinase 1 (RACK1) pathway in the CAR-mediated induction of Cyp2b10 in mice livers. SIGNIFICANCE STATEMENT: This is the first report of involvement of PKN in the transcriptional regulation of P450s. The elucidation of mechanisms responsible for induction of P450s could help optimize the pharmacotherapy and improve drug development. We examined whether the mRNA and protein levels and activities of P450s were altered in double-mutant mice harboring both PKN1 kinase-negative knock-in and PKN3 knockout mutations. PKN1/3 negatively regulates CAR-mediated induction of Cyp2b10 through phosphorylation of a signaling molecule in the Src-RACK1 pathway.
• Increased brain penetration of diphenhydramine and memantine in rats with adjuvant-induced arthritis

  Kawase A; Kazaoka A; Shimada H; Iwaki M

  Brain Res 2021 [Refereed]
  
• NHERF1/EBP50 as a target for modulation of MRP function in HepG2 cells

  Kawase A; Hirosoko M; Sugihara Y; Koyama Y; Fukae A; Shimada H; Iwaki M

  Pharmaceuticals 2021 [Refereed]
  
• Increased Penetration of diphenhydramine in brain via proton-coupled organic cation antiporter in rats with lipopolysaccharide-induced inflammation

  Kawase A; Chuma T; Irie K; Kazaoka A; Kakuno A; Matsuda N; Shimada H; Iwaki M

  Brain Behav Immun Health 10 100188 - 100188 2021 [Refereed]
   

  Uptake transporters in brain microvascular endothelial cells (BMECs) are involved in the penetration of basic (cationic) drugs such as diphenhydramine (DPHM) into the brain. Lipopolysaccharide (LPS)-induced inflammation alters the expression levels and activities of uptake transporters, which change the penetration of DPHM into the brain. A brain microdialysis study showed that the unbound brain-to-plasma partition coefficient (K p,uu,brain) for DPHM in LPS rats was approximately two times higher than that in control rats. The transcellular transport of DPHM to BMECs was increased when BMECs were cultured with serum from LPS rats. Compared with control rats or BMECs, the brain uptake of DPHM in LPS rats was increased and the intracellular accumulation of DPHM was increased under a high intracellular pH in BMECs from LPS rats, respectively. Treatment of BMECs with transporter inhibitors or inflammatory cytokines had little impact on the intracellular accumulation of DPHM in BMECs. This study suggests that LPS-induced inflammation promotes unidentified proton-coupled organic cation (H+/OC) antiporters that improve the penetration of DPHM into rat brain via the blood-brain barrier.
• マウスにおけるシトクロムP450誘導過程におけるプロテインキナーゼNファミリーの役割

  川瀬 篤史; 向井 秀幸; 立石 駿介; 黒田 真太郎; 松田 尚也; 佐藤 亮介; 島田 紘明; 杉浦 麗子; 岩城 正宏

  日本薬学会年会要旨集 (公社)日本薬学会 140年会 27X - pm02 0918-9823 2020/03
• The regulatory mechanism involved in the prostaglandin E2 disposition in carbon tetrachloride-induced liver injury.

  Hiroaki Shimada; Ryota Hashimoto; Aya Aoki; Saya Yamada; Ken-Ichi Oba; Atsushi Kawase; Takeo Nakanishi; Masahiro Iwaki

  Prostaglandins, leukotrienes, and essential fatty acids 155 102081 - 102081 2020/02 [Refereed]
   

  Prostaglandin E2 (PGE2) exhibits hepatoprotective effects against various types of liver injury. However, there is little information on the disposition of endogenous PGE2 during liver injury. In the present study, we attempted to elucidate the mechanism involved in regulating PGE2 distribution during liver injury. Carbon tetrachloride (CCl4) was used to establish a liver injury mouse model. PGE2 was measured by LC-MS/MS. The plasma and hepatic PGE2 levels were significantly increased at 6 to 48 h after CCl4 treatment. The ratio of plasma levels of 13,14-dihydro-15-ketoPGE2 (PGEM), a major PGE2 metabolite, to PGE2 decreased significantly after CCl4 treatment. PGE2 synthesis and expression of enzymes related to PGE2 production were not induced, while the activity and mRNA expression of 15-prostaglandin dehydrogenase (15-PGDH/Hpgd), a major enzyme for PGE2 inactivation, decreased significantly in the liver of CCl4-treated mice compared to that of vehicle-treated control. The plasma and hepatic PGE2 levels were negatively correlated with the hepatic mRNA expression levels of Hpgd. Although the mRNA expression of organic anion transporting polypeptide 2A1 (OATP2A1/Slco2a1), a major PGE2 transporter, was upregulated, other hepatic OATPs decreased significantly at 24 h after CCl4 treatment. Immunohistochemical analysis indicated that 15-PGDH was mainly expressed in endothelial cells and that OATP2A1 was expressed at least in endothelial cells and Kupffer cells in the liver. These results suggest that the decreased 15-PGDH expression in hepatic endothelial cells is the principal mechanism for the increase in hepatic and plasma PGE2 levels due to the CCl4-induced liver injury.
• Changes in radixin expression and interaction with efflux transporters in the liver of adjuvant-induced arthritic rats

  Kawase A; Nakasaka, M; Bando H; Yasuda S; Shimada H; Iwaki M

  Inflammation 43 (1) 85 - 94 0360-3997 2020 [Refereed]
   

  Scaffold proteins such as radixin help to modulate the plasma membrane localization and transport activity of the multidrug resistance-associated protein 2 (MRP2/ABCC2) and P-glycoprotein (P-gp/ABCB1) efflux transporters in the liver. We examined changes in radixin expression and interaction with efflux transporters in adjuvant-induced arthritic (AA) rats, an animal model of rheumatoid arthritis, as well as in human liver cancer (HepG2) cells because inflammation affects drug pharmacokinetics via the efflux transporters. The expression levels of radixin and phosphorylated radixin (p-radixin) were measured 24 h after treatment with inflammatory cytokines comprising tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 or sodium nitroprusside (SNP; a nitric oxide donor). The protein levels of radixin, MRP2, and P-gp in the rat liver were next examined. We also investigated whether inflammation affected the formation of complexes between radixin and MRP2 or P-gp. The mRNA and protein levels of radixin in HepG2 cells were significantly decreased by TNF-α treatment, while minimal changes were observed after treatment with IL-1β, IL-6 or SNP. TNF-α also significantly decreased the protein levels of p-radixin, suggesting that TNF-α inhibited the activation of radixin and thereby reduced the activity of the efflux transporters. Complex formation of radixin with MRP2 and P-gp was significantly decreased in AA rats but this was reversed by prednisolone and dexamethasone treatment, indicating that decreased interactions of radixin with MRP2 and P-gp likely occur during liver inflammation. These data suggest that liver inflammation reduces radixin function by decreasing its interactions with MRP2 and P-gp.
• Drug interactions between tacrolimus and clotrimazole troche: a data mining approach followed by a pharmacokinetic study.

  Takaya Uno; Kyoichi Wada; Kouichi Hosomi; Sachi Matsuda; Megumi Morii Ikura; Hiromi Takenaka; Nobue Terakawa; Akira Oita; Satoshi Yokoyama; Atsushi Kawase; Mitsutaka Takada

  European journal of clinical pharmacology 76 (1) 117 - 125 0031-6970 2020/01 [Refereed]
   

  PURPOSE: This study investigated the effects of clotrimazole troche on the risk of transplant rejection and the pharmacokinetics of tacrolimus. METHODS: The data mining approach was used to investigate whether the use of clotrimazole increased the risk of transplant rejection in patients receiving tacrolimus therapy. Patient data were acquired from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) from the first quarter of 2004 to the end of 2017. Next, we retrospectively investigated the effect of clotrimazole troche on tacrolimus pharmacokinetics in seven patients who underwent heart transplantation between March and December 2017. RESULTS: The FAERS subset data indicated a significant association between transplant rejection and tacrolimus with clotrimazole [reporting odds ratio 1.92, 95% two-sided confidence interval (95% CI) 1.43-2.58, information component 0.81, 95% CI 0.40-1.23]. The pharmacokinetic study demonstrated a significant correlation between trough concentration (C0) and area under the concentration-time curve of tacrolimus after discontinuation of clotrimazole (R2 = 0.60, P < 0.05) but not before its discontinuation. Furthermore, the median clearance/bioavailability of tacrolimus after discontinuation of clotrimazole was 2.2-fold greater than that before its discontinuation (0.27 vs. 0.59 L/h/kg, P < 0.05). The median C0 decreased from 10.7 ng/mL on the day after discontinuation of clotrimazole to 6.5 ng/mL at 1 day and 5.3 ng/mL at 2 days after its discontinuation. CONCLUSION: Immediate dose adjustments of tacrolimus may be beneficial to avoid transplant rejection when clotrimazole troche is added or discontinued.
• Inhibitory Effect of Ocimum gratissimum Leaf Extract on Postprandial Increase of Blood Glucose

  Shimada, Hiroaki; Kuma, Chiaki; Iseri, Taichi; Matsumura, Shin-ichi; Kawase, Atsushi; Matsuura, Masayoshi; Iwaki, Masahiro

  NATURAL PRODUCT COMMUNICATIONS SAGE PUBLICATIONS INC 14 (10) 1934-578X 2019/10 [Refereed]
   

  The tea of Ocimum gratissimum (OG) leaves has been commonly consumed by people living in Ishigaki Island, Okinawa prefecture, Japan, and is considered to be effective for improving diabetes mellitus. In this study, we aimed to clarify the inhibitory potential of OG leaves extract (OG-ext) on gastrointestinal glucose absorption and to provide theoretical evidence for the anti-hyperglycemic effect of OG-ext. The increase of blood glucose after oral administration of alpha-starch and glucose in mice was suppressed by co-administration of OG-ext. An in vitro enzymatic assay suggested that amylase and maltase were inhibited weakly by the addition of OG-ext. In Caco-2 cells, a human intestinal epithelial model, the sodium-dependent glucose transporter (SGLT) 1-mediated uptake of fluorescence glucose analog was inhibited significantly by the addition of OG-ext in a concentration-dependent manner. These results indicate that the inhibitory effect on SGLT1 is one of the mechanisms of the anti-hyperglycemic effect of the tea of OG leaves.
• Clotrimazole troches can alter everolimus pharmacokinetics in post-transplant patients: A case report.

  Takaya Uno; Kyoichi Wada; Sachi Matsuda; Megumi Ikura; Hiromi Takenaka; Nobue Terakawa; Akira Oita; Satoshi Yokoyama; Atsushi Kawase; Kouichi Hosomi; Mitsutaka Takada

  British journal of clinical pharmacology 85 (9) 2176 - 2178 2019/09 [Refereed]
  
• Decrease in Multidrug Resistance-associated Protein 2 Activities by Knockdown of Phosphatidylinositol 4-phosphate 5-kinase in Hepatocytes and Cancer Cells

  Atsushi Kawase; Yuta Inoue; Miho Hirosoko; Yuka Sugihara; Hiroaki Shimada; Masahiro Iwaki

  Journal of Pharmacy & Pharmaceutical Sciences 2019 [Refereed]
  
• Changes in transporters and metabolizing enzymes in the livers of rats with bile duct ligation.

  Atsushi Kawase; Akira Kazaoka; Rei Yamamoto; Risa Minakata; Hiroaki Shimada; Masahiro Iwaki

  Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 22 (1) 457 - 465 2019 [Refereed]
   

  PURPOSE: Bile duct ligation (BDL) in experimental animals is widely used as an animal model of liver cholestasis and fibrosis. The transcriptional process and plasma membrane localization of transporters are regulated by nuclear receptors and scaffold proteins, respectively. However, the detailed changes of these factors in the livers of BDL rats remain unclear. To clarify the effects of BDL on the levels of transporters and metabolizing enzymes, nuclear receptors, and scaffold proteins, we investigated changes in mRNA and protein levels of livers from BDL rats. METHODS: Membrane proteins and microsomes were prepared from rats with BDL. The mRNA levels of transporters and nuclear receptors in livers of control and BDL rats were examined by real-time reverse transcription polymerase chain reaction. The protein levels of transporters, metabolizing enzymes and scaffold proteins in membrane proteins and microsomes were determined by liquid chromatography-tandem mass spectrometry-based targeted proteomics. RESULTS: Mdr1a mRNA was significantly decreased at 1 and 2 weeks of BDL. The mRNA levels of MRP2 were significantly decreased. The mRNA levels of nuclear receptors were significantly decreased in livers of 1-week BDL rats. The protein levels of P-gp were significantly increased by BDL. Regarding scaffold proteins, the protein levels of ezrin, moesin and EBP50 were significantly decreased at 2 weeks of BDL. The protein levels of radixin were significantly increased at 1 week of BDL. In 1-week BDL rats, the protein levels of metabolizing enzymes such as CYP and UGT were significantly decreased. CONCLUSIONS: This study reports the comprehensive changes of transporters, metabolizing enzymes, nuclear receptors, and ezrin/radixin/moesin proteins in the livers of BDL rats. The expression levels of nuclear receptors and radixin that regulate the transcription and localization of CYP and/or transporters were decreased by BDL.
• Radixin knockdown improves the accumulation and efficiency of methotrexate in tumor cells

  Atsushi Kawase; Yuta Inoue; Sayaka Nakazaki; Erika Koizumi; Masahiro Iwaki

  Oncol Rep 42 283 - 290 2019 [Refereed]
  
• Prediction of hepatic clearance of stereoselective metabolism of carvedilol in liver microsomes and hepatocytes of Sprague-Dawley and cytochrome P450 2D-dificient Dark Agouti rats

  Masahiro Iwaki; Toshiro Niwa; Hiroyuki Tanaka; Atsushi Kawase; Hiroshi Komura

  22 72 - 84 2019 [Refereed]
  
• Involvement of diclofenac acyl-b-d-glucuronide in diclofenac-induced cytotoxicity in glutathione-depleted isolated murine hepatocytes co-cultured with peritoneal macrophages

  Atsushi Kawase; Ayaka Kaneto; Mao Ishibashi; Akihiro Kobayashi; Hiroaki Shimada; Masahiro Iwaki

  29 (3) 203 - 210 2019 [Refereed]
  
• Effects of clotrimazole on tacrolimus pharmacokinetics in patients with heart transplants with different CYP3A5 genotypes.

  Takaya Uno; Kyoichi Wada; Sachi Matsuda; Yuka Terada; Nobue Terakawa; Akira Oita; Satoshi Yokoyama; Atsushi Kawase; Kouichi Hosomi; Mitsutaka Takada

  European journal of clinical pharmacology 75 (1) 67 - 75 2019/01 [Refereed]
   

  PURPOSE: This study aimed to investigate the effects of clotrimazole on the pharmacokinetics of tacrolimus in Japanese patients with heart transplants with different CYP3A5 genotypes. METHODS: Twenty-six patients who underwent heart transplantation between June 2012 and July 2017 were enrolled in this retrospective study. The CYP3A5 (rs776746; CYP3A5*3) genotype was determined after monitoring and analysing tacrolimus blood concentrations. The pharmacokinetic profile of tacrolimus was examined before and after the discontinuation of clotrimazole and in patients with different CYP3A5 genotypes. RESULTS: The CYP3A5*1/*1, *1/*3 and *3/*3 genotypes were detected in 2, 8 and 16 patients, respectively. After clotrimazole was discontinued, the CYP3A5 expresser (CYP3A5*1/*1 or *1/*3) group had a 3.3-fold median increase in apparent oral clearance of tacrolimus (0.27 vs. 0.89 L/h/kg, P = 0.002) compared with the CYP3A5 non-expresser (CYP3A5*3/*3) group with a 2.2-fold median increase (0.18 vs. 0.39 L/h/kg, P < 0.0001). Significant correlations were observed between C0 and area under the concentration-time curve (AUC0-12) of tacrolimus after the discontinuation of clotrimazole in the CYP3A5 expresser and non-expresser groups, respectively (R2 = 0.49 and 0.42, all P < 0.05), but not before the discontinuation of clotrimazole. CONCLUSION: The effects of clotrimazole on tacrolimus pharmacokinetics in the CYP3A5 expresser patients were significantly greater than those in the CYP3A5 non-expresser patients. In addition, clotrimazole disturbed the correlation between C0 and AUC0-12 of tacrolimus. Careful dose adjustment of tacrolimus based on CYP3A5 genotypes may be beneficial for the patients with heart transplants who are concomitantly treated with clotrimazole.
• Impact of the CYP3A5*1 Allele on the Pharmacokinetics of Tacrolimus in Japanese Heart Transplant Patients

  Takaya Uno; Kyoichi Wada; Sachi Matsuda; Yuka Terada; Akira Oita; Atsushi Kawase; Mitsutaka Takada

  European Journal of Drug Metabolism and Pharmacokinetics Springer-Verlag France 43 (6) 1 - 9 2107-0180 2018/04 [Refereed]
   

  Background and Objective: Tacrolimus, a major immunosuppressant used after transplantation, is associated with large interindividual variation involving genetic polymorphisms in metabolic processes. A common variant of the cytochrome P450 (CYP) 3A5 gene, CYP3A5*3, affects blood concentrations of tacrolimus. However, tacrolimus pharmacokinetics at the early stage of transplantation have not been adequately studied in heart transplantation. We retrospectively examined the impact of the CYP3A5 genotype on tacrolimus pharmacokinetics at the early stage of heart transplantation. Methods: The tacrolimus pharmacokinetic profile was obtained from 65 patients during the first 5 weeks after heart transplantation. Differences in the patients’ characteristics and tacrolimus pharmacokinetic parameters between the CYP3A5 expresser (*1/*1 or *1/*3 genotypes) and non-expresser (*3/*3 genotype) groups were assessed by the Chi-square test, Student’s t test, or Mann–Whitney U test. Results: The CYP3A5 *1/*1, *1/*3, and *3/*3 genotypes were detected in 5, 22, and 38 patients, respectively. All patients started clotrimazole therapy approximately 1 week after starting tacrolimus. Apparent clearance and dose/weight to reach the target trough concentration (C0) were significantly higher in the expresser group than in the non-expresser group (0.32 vs. 0.19 L/h/kg, p = 0.0003 0.052 vs. 0.034 mg/kg/day, p = 0.0002) there were no significant differences in the area under the concentration-time curve from 0 to 12 h (AUC0–12) and concentrations at any sampling time point between the two groups. Conclusion: Similar concentration–time curves for tacrolimus were obtained in the expresser and non-expresser groups by dose adjustment based on therapeutic drug monitoring. These results demonstrate the importance of the CYP3A5 genotype in tacrolimus dose optimization based on therapeutic drug monitoring after heart transplantation.
• 各世代のとろみ調整剤が血糖値に与える影響

  松浦正佳; 島田紘明; 岸本理咲; 藤本和佳; 大鳥徹; 川瀬篤史; 岩城正宏

  薬局薬学 10 (1) 131 - 139 2018/04 [Refereed]
  
• Correlation between glucuronidation and covalent adducts formation with proteins of nonsteroidal anti-inflammatory drugs

  Hiroaki Shimada; Yuri Kobayashi; Sakiko Tanahashi; Atsushi Kawase; Taro Ogiso; Masahiro Iwaki

  European Journal of Pharmaceutical Sciences Elsevier B.V. 112 132 - 138 1879-0720 2018/01 [Refereed]
   

  Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause idiosyncratic liver injury. Mechanisms involved in NSAID-induced liver injury are complex. Previous studies have suggested that acyl glucuronide of NSAIDs (NSAIDs-Glu) plays an important role in the development of liver injury via covalently binds to proteins and the resultant adduct induces immunological toxicity. As only some NSAIDs-Glu are commercially available, the evaluation of covalent protein adduct formation using ready-made NSAIDs-Glu is difficult and inconvenient. Moreover, glucuronidation potency varies with the NSAID, including stereoisomers. Therefore, in this study, we simultaneously examined the glucuronidation and covalent adduct formation using enantiomers of parent NSAIDs (ibuprofen, naproxen, pranoprofen, ketoprofen, and flurbiprofen) in rat liver microsomes. Glucuronides and covalent adducts were quantified by HPLC. The amount of covalent adduct increased with NSAIDs-Glu formation in the rat liver microsomes in a time-dependent manner. A significant positive correlation was observed between the AUC of NSAIDs-Glu and that of covalent adduct, except ketoprofen. Although ketoprofen exhibited the highest glucuronidation rate among the NSAIDs investigated, the amount of covalent adduct was similar to that for pranoprofen, which had the lowest glucuronidation rate. Thus, it may be difficult for ketoprofen glucuronide to covalently bind with proteins in the rat liver microsomes. Our results suggested that the amount of glucuronide formed is a key factor in predicting covalent bond formation with protein in NSAIDs, in addition to degradability and bindability with proteins of NSAIDs-Glu. Further studies are required to confirm the relationship between the tendency of glucuronidation and the formation of covalent adducts of NSAIDs.
• Impact of the CYP3A5 genotype on the pharmacokinetics of tacrolimus in Japanese heart transplant patients

  Takaya Uno; Kyoichi Wada; Sachi Matsuda; Yuka Terada; Akira Oita; Atsushi Kawase; Mitsutaka Takada

  Eur J Drug Metabol Pharmacokinet 2018 [Refereed]
  
• Relative contribution of rat CYP isoforms responsible for stereoselective metabolism of carvedilol

  Masahiro Iwaki; Toshiro Niwa; Yukiko Nakamura; Atsushi Kawase; Hiroshi Komura

  Journal of Toxicological Sciences Japanese Society of Toxicology 43 (1) 59 - 63 0388-1350 2018 [Refereed]
   

  The relative contribution of cytochrome P450 (CYP) isoforms responsible for carvedilol (CAR) oxidation in rats were evaluated in order to compare with that of reported human CYPs responsible for the metabolism of CAR enantiomers. The depletion of CAR enantiomers by recombinant CYPs and the effects of CYP-selective inhibitors on the depletion catalyzed by rat liver microsomes (RLM) was determined. Quinine (rat CYP2D inhibitor) markedly inhibited the metabolism of both R- and S-CAR by RLM. The metabolism of S-CAR was inhibited more than that of R-CAR by furafylline, (a CYP1A2 inhibitor, 53.5% vs 11.3%), α-naphthoflavone (a CYP1A2 inhibitor, 64.5% vs 33.6%), and ketoconazole (a CYP3A inhibitor, 87.1% vs 51.2%). Among the CYPs examined, CYP2D2 showed the highest metabolic activities against both the enantiomers. R-CAR was mainly metabolized by CYP2D2 and CYP3A2. CYP2C11 and CYP3A1, in addition to CYP2D2 and CYP3A2 showed higher metabolic activities against S-CAR than that against R-CAR. These results suggest that CYP2D2 predominantly catalyzed R-CAR metabolism, whereas CYP2D2 and CYP3A1/2 catalyzed S-CAR metabolism in rats.
• 各世代のとろみ調整剤が血糖値に与える影響

  松浦正佳; 島田紘明; 岸本理咲; 藤本和佳; 大鳥徹; 川瀬篤史; 岩城正宏

  The Journal of Community Pharmacy and Pharmaceutical Sciences 10 1 - 9 2018 [Refereed]
  
• Profiling of hepatic metabolizing enzymes and nuclear receptors in rats with adjuvant arthritis by targeted proteomics

  Atsushi Kawase; Shunsuke Tateishi; Akira Kazaoka

  Biopharm Drug Dispos 39 (6) 308 - 314 2018 [Refereed]
  
• Major constituents of Cistanche tubulosa, echinacoside and acteoside, inhibit sodium-dependent glucose cotransporter 1-mediated glucose uptake by intestinal epithelial cells

  Shimada, Hiroaki; Urabe, Yuichi; Okamoto, Yuhei; Li, Zheng; Kawase, Atsushi; Morikawa, Toshio; Tu, Pengfei; Muraoka, Osamu; Iwaki, Masahiro

  JOURNAL OF FUNCTIONAL FOODS ELSEVIER SCIENCE BV 39 91 - 95 1756-4646 2017/12 [Refereed]
   

  Echinacoside (ECH) and acteoside (ACT), the major constituents of Cistanche tubulosa, suppress the increase in postprandial blood glucose level. Although ECH and ACT have been reported to weakly inhibit alpha-glucosidases, the underlying mechanism remains unclear. Therefore, we focused on the regulatory mechanism of dietary glucose absorption: In this study, we aimed to clarify the inhibitory effects of ECH and ACT on sodium-dependent glucose cotransporter (SGLT) 1-mediated gastrointestinal glucose absorption. Uptake experiments were performed using human intestinal Caco-2 cells and the fluorescence glucose analogue, 2-deoxy-2-[(7-nitro-2,1,3benzoxadiazol-4-yDaminc]-n-glucose (2-NBDG). Sodium-dependent 2-NBDG uptake was successfully estimated and this uptake was completely inhibited by an SGLT inhibitor phlorizin. ECH and ACT inhibited sodium-dependent 2-NBDG uptake in a concentration-dependent manner. However, this inhibition was not observed under sodium-free condition. This study suggested that the inhibitory effects of ECH and ACT on SGLT1-mediated glucose uptake contribute to suppression of increased postprandial blood glucose level.
• Effects of High-cholesterol Diet on Pravastatin Disposition in the Perfused Rat Liver

  Atsushi Kawase; Ayumi Handa; Masahiro Iwaki

  EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS SPRINGER FRANCE 42 (3) 519 - 526 0378-7966 2017/06 

  Background and Objectives Various nutrients modulate the expression of transporters; however, the effect of a high-cholesterol (HC) diet on the expression and function of hepatic transporters remains unclear. Here, we examined the effects of an HC diet on drug disposition via hepatic transporters, including organic anion-transporting polypeptide (Oatp), multidrug resistance-associated protein (Mrp), and bile salt export pump (Bsep). Methods In situ perfused rat liver system was performed. The levels of pravastatin, which is taken up into hepatocytes by Oatp and excreted into bile by Mrp2, in the perfusate and in bile were measured using high-performance liquid chromatography. Results Pravastatin was rapidly eliminated in control and HC rats; however, the cumulative amounts of excreted in bile were significantly higher in HC rats than in controls possibly because of the enhanced bile flow in HC rats (0.93 +/- 0.05 mu L/min in control, and 1.22 +/- 0.18 mu L/min in HC). Real-time reverse-transcriptase polymerase chain reaction (PCR) and western blot assessment of the mRNA and protein levels of hepatic transporters showed a significant downregulation of the Oatp1a1 and Bsep proteins in HC rats, whereas no differences in Mrp2 and Mrp3 levels were observed between HC and control rats. The analysis of the localization of Mrp2 on the canalicular membrane by immunofluorescence showed no changes in HC rats, although Mrp2 was readily internalized from the canalicular membrane under specific conditions. Conclusions The findings of the present study indicate that the HC diet affected the biliary excretion of pravastatin concomitant with increased bile flow, despite minimal effects on the expression of hepatic transporters. The HC diet could promote the biliary excretion of other drugs and metabolites that are substrates of Mrp2 and Bsep.
• Involvement of Reactive Metabolites of Diclofenac in Cytotoxicity in Sandwich-Cultured Rat Hepatocytes

  Atsushi Kawase; Ryota Hashimoto; Mai Shibata; Hiroaki Shimada; Masahiro Iwaki

  INTERNATIONAL JOURNAL OF TOXICOLOGY SAGE PUBLICATIONS INC 36 (3) 260 - 267 1091-5818 2017/05 

  Background and Objectives: Diclofenac (DIC) is metabolized to reactive metabolites such as diclofenac acyl--d-glucuronide (DIC-AG). It is possible that such reactive metabolites could cause tissue damage by formation of covalent protein adducts and other modification of cellular proteins or by induction of immune responses against its covalent protein adducts. However, the detailed mechanisms of idiosyncratic drug-induced liver injury (DILI) have been unclear. The objective is to clarify the involvement of DIC-AG and 4hydroxydiclofenac (4OH-DIC) in acute DILI.Methods:We examined the effects of inhibiting DIC-AG and 4OH-DIC production on covalent protein adduct formation and lactate dehydrogenase leakage using sandwich-cultured rat hepatocytes (SCRHs).Results:After pretreatment of SCRH with (-)-borneol (BOR, a uridine diphosphate (UDP)-glucuronosyltransferase inhibitor) or sulfaphenazole (SUL, a cytochrome P450 2C9 inhibitor) for 30 minutes, intracellular concentrations of DIC, DIC-AG, and 4OH-DIC were determined after further treating cells with 300 M DIC for 3 hours. The decreased levels of reactive metabolites caused by BOR or SUL pretreatment resulted in decreased lactate dehydrogenase leakage from SCRH, although the formation of covalent protein adducts was not affected.Conclusion:These results suggested that both DIC-AG and 4OH-DIC may be involved in acute cytotoxicity by DIC.
• Effects of Adjuvant-Induced Inflammation on Disposition of Diclofenac and Its Metabolites in Perfused Rat Liver

  Misato Uraki; Atsushi Kawase; Hiroyuki Sayama; Yuka Matsushima; Masahiro Iwaki

  JOURNAL OF PHARMACEUTICAL SCIENCES WILEY 106 (4) 1175 - 1182 0022-3549 2017/04 

  The reactive metabolites of diclofenac (DF) such as 1-O-acyl glucuronide (DF-Glu) are hypothesized to result in idiosyncratic hepatotoxicity. However, it is unclear whether inflammation affects the hepatic disposition of DF and its metabolites. To clarify the alterations in the disposition of DF and its metabolites in inflammatory conditions, we performed in situ perfused rat liver experiments. Using adjuvant arthritis rats as a model of inflammation, the elimination of DF, 4'-hydroxydiclofenac, and DF-Glu from the perfusate was observed to be delayed in comparison with the control. Parameter sensitivity analysis for hepatic DF disposition revealed that the area under the plasma concentration-time curve (AUC) and the maximum concentration (C-max) of DF-Glu in the liver markedly increased along with a decrease in intrinsic excretion clearance of DF-Glu (CLint,bile,Glu) and an increase in intrinsic glucuronidation clearance (CLint,Glu) of DF-Glu. It is possible that the elimination of DF-Glu from the perfusate in adjuvant arthritis rats was delayed via reduction of biliary excretion of DF-Glu. (C) 2017 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
• Stereoselective Pharmacokinetics and Chiral Inversion of Ibuprofen in Adjuvant-induced Arthritic Rats

  Hiroyuki Ikuta; Atsushi Kawase; Masahiro Iwaki

  DRUG METABOLISM AND DISPOSITION AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS 45 (3) 316 - 324 0090-9556 2017/03 

  2-Arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drugs are commonly used in racemic mixtures (rac) for clinical use. 2-APA undergoes unidirectional chiral inversion of the in vivo inactive R-enantiomer to the active S-enantiomer. Inflammation causes the reduction of metabolic activities of drug-metabolizing enzymes such as cytochrome P450 (P450) and UDP-glucuronosyltransferase. However, it is unclear whether inflammation affects the stereoselective pharmacokinetics and chiral inversion of 2-APA such as ibuprofen (IB). We examined the effects of inflammation on the pharmacokinetics of R-IB and S-IB after intravenous administration of rac-IB, R-IB, and S-IB to adjuvant-induced arthritic (AA) rats, an animalmodel of inflammation. The plasma protein binding of rac-IB, glucuronidation activities for R-IB and S-IB, and P450 contents of liver microsomes in AA rats were determined. Total clearance (CLtot) of IB significantly increased in AA rats, although the glucuronidation activities for IB, and P450 contents of liver microsomes decreased in AA rats. We presumed that the increased CLtot of IB in AA rats was caused by the elevated plasma unbound fraction of IB due to decreased plasma albumin levels in AA rats. Notably, CLtot ofR-IB but not S-IB significantly increased in AA rats after intravenous administration of rac-IB. These results suggested that AA could affect drug efficacies after stereoselective changes in the pharmacokinetics of R-IB and S-IB.
• Stability evaluations of montelukast tablets under conditions of single dose packaging

  Masayoshi Matsuura; Toru Otori; Atsushi Kawase; Hiroaki Shimada; Hideyuki Nakanishi; Masahiro Iwaki

  Int J Pharm Tech 9 (4) 31079 - 31087 2017 [Refereed]
  
• Stereoselective hepatic disposition of ibuprofen in the perfused liver of rat with adjuvant-induced arthritis

  Misato Uraki; Atsushi Kawase; Masahiro Iwaki

  XENOBIOTICA TAYLOR & FRANCIS LTD 47 (11) 943 - 950 0049-8254 2017 

  1. The effects of adjuvant-induced arthritis (AA) on the stereoselective hepatic disposition and chiral inversion of "profens" have scarcely been investigated. Ibuprofen (IB) undergoes unidirectional chiral inversion from R-IB to S-IB and is metabolized to IB-glucuronide (IB-Glu). 2. We used an in situ perfused rat liver system to clarify the effects of inflammation on the metabolic activities and chiral inversion of IB without protein binding. 3. After dosing of R-IB, AA had minimal effect on the elimination of R-IB from the perfusate. Larger amounts of S-IB-Glu than R-IB-Glu were observed in the bile at the dose of 2.4 and 4.8 mol. However, after dosing of S-IB, the elimination of S-IB from the perfusate in AA rats was delayed, indicating a significant decrease in the hepatic clearance in AA rats. The cumulative biliary excretion of S-IB-Glu in AA rats was promoted after dosing with S-IB. There was little difference between the chiral inversion ratios of the control and AA rats. 4. The present study demonstrated that AA results in the delayed elimination of S-IB, the active form, without changes to the chiral inversion ratio. Thus, further attention to the altered stereoselective pharmacokinetics of IB during inflammation is required.
• Development of hemiacetal esterified levofloxacin to prevent chelation with metal-containing drugs

  Toru Otori; Sumio Matzno; Atushi Kawase; Masahiro Iwaki; Tetsutaro Kimachi; Keiji Nishiwaki; William C. Figoni; Ryuta Tominaga; Mai Asahide; Mayumi Nishikata; Yoshikazu Ishii; Kenji Matsuyama

  JOURNAL OF PHARMACY AND PHARMACOLOGY WILEY-BLACKWELL 68 (12) 1527 - 1534 0022-3573 2016/12 

  ObjectivesTo avoid the chelate formation between levofloxacin (LVFX) and aluminium hydroxide in gastrointestinal tract, an ethoxycarbonyl 1-ethyl hemiacetal ester of levofloxacin (LVFX-EHE) was synthesised as a prodrug. MethodsThe effects of aluminium hydroxide on the bioavailability of LVFX following oral administration of LVFX-EHE were investigated in rats. Furthermore, the effects of aluminium hydroxide on small intestinal absorption of LVFX and LVFX-EHE when subjected to a hydrolysis experiment using in situ everted gut sac were investigated, and the minimal inhibitory concentrations (MICs) of LVFX and LVFX-EHE for various intestinal bacteria were measured. Key findingsWhen LVFX-EHE was co-administered with and without aluminium hydroxide, the AUC(0-4 h) values of LVFX hydrolysed from LVFX-EHE were similar to that of LVFX alone. In everted gut sac experiments, LVFX-EHE was efficiently absorbed even in the presence of aluminium ions after 1 h of incubation, whereas the absorption of LVFX decreased significantly in the presence of aluminium ions. MIC values of LVFX-EHE were far higher than LVFX. ConclusionsThis study suggests the benefit of ethoxycarbonyl 1-ethyl hemiacetal esterification of the carboxyl group of new quinolone as a prodrug which is able to avoid chelate formation.
• Application of substrate depletion assay to evaluation of CYP isoforms responsible for stereoselective metabolism of carvedilol

  Masahiro Iwaki; Toshiro Niwa; Saya Bandoh; Megumi Itoh; Hitomi Hirose; Atsushi Kawase; Hiroshi Komura

  DRUG METABOLISM AND PHARMACOKINETICS JAPANESE SOC STUDY XENOBIOTICS 31 (6) 425 - 432 1347-4367 2016/12 

  To evaluate the relative contribution of cytochrome P450 (CYP) isoforms responsible for carvedilol (CAR) oxidation, enantioselective metabolism of CAR was investigated in human liver microsomes (HLMs) and recombinant human CYPs by using the substrate depletion assay. CYP2D6 exhibited the highest contribution to the metabolism of R-CAR, followed by CYP3A4, CYP1A2, and CYP2C9, whereas the metabolism of the S-enantiomer was mainly mediated by CYP1A2, followed by CYP2D6 and CYP3A4. In HLMs, metabolism of R-and S-CAR was markedly inhibited by quinidine; R-CAR metabolism (57-61% decrease) was more inhibited than S-CAR metabolism (37-43% decrease), and furafylline and ketoconazole almost equally inhibited metabolism of both enantiomers by 25-32% and 30-50%, respectively. The absence of CYP2D6 in a mixture of five major recombinant CYP isoforms at the approximate ratio as in HLMs resulted in a 42% and 25% decrease in the metabolic activities for R-and S-CAR, respectively. Moreover, the absence of CYP1A2 in the mixture resulted in a 16% and 39% decrease in the metabolic activities for R-and S-CAR, respectively. Our results suggest the stereoselective metabolism of CAR is determined by not only the activity of CYP2D6 but also of CYP1A2 and CYP3A4. (C) 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
• Effects of duration of phenytoin administration on mRNA expression of cytochrome P450 and P-glycoprotein in the liver and small intestine of rats

  Atsushi Kawase; Hiroyuki Tanaka; Toru Otori; Kenji Matsuyama; Masahiro Iwaki

  ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES HONG KONG ASIAMED PUBLISH HOUSE 11 (5) 662 - 667 1818-0876 2016/10 

  Phenytoin (5,5-diphenylhydantoin; DPH) induces expression of cytochromes P450 (CYPs). Interactions between DPH and tacrolimus suggested that the persistence of CYP induction after discontinuation of DPH is dependent on the history of administration and dosing period of DPH. However, the relationship between the duration of DPH administration and expression of CYPs in the liver and small intestine of rats is not known. Alterations in levels of P-glycoprotein (P-gp; MDR1; ABCB1) as well as CYPs cause drug interactions in the small intestine. We examined the effects of the duration of DPH administration on expression of CYPs and P-gp in the liver and small intestine of rats. Rats were treated with DPH (100 mg/kg, peroral (p.o.) twice a day (b.d.)) for 2, 4, 8, and 16 d. mRNA levels of CYPs and P-gp were examined using the total RNA extracted from the liver and duodenum 2 h and 24 h after the final administration of DPH. CYP3A activities were determined using microsomes. DPH administration for 2 d and 4 d markedly increased mRNA levels of CYPs such as CYP3A1, CYP3A2, CYP2B1, and CYP2B2 in the liver. A relatively long duration of DPH administration (8 d and 16 d) resulted in abolition of the induction of hepatic CYP but increased CYP3A activities were maintained. These results suggest that the duration of DPH administration could be an important determinant of hepatic CYP induction. (C) 2016 Shenyang Pharmaceutical University. Production and hosting by Elsevier B.V.
• Impact of a high-cholesterol diet on expression levels of Niemann-Pick C1-like 1 and intestinal transporters in rats and mice

  Atsushi Kawase; Yasuha Araki; Yukiko Ueda; Sayaka Nakazaki; Masahiro Iwaki

  EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS SPRINGER FRANCE 41 (4) 457 - 463 0378-7966 2016/08 

  Niemann-Pick C1-like 1 (NPC1L1), ATP-binding cassette (ABC)G5, and ABCG8 are all involved in intestinal cholesterol absorption. It is unclear whether a high-cholesterol (HC) diet affects the expression of these transporters in rats and mice as well as humans. We examined the effects of an HC diet on their expression in small intestine and the differences between rats and mice in the responsive of this expression to an HC diet. In addition to these transporters, alterations in six representative drug and nutrient transporters (multidrug resistance-associated protein, breast cancer resistance protein, peptide transporter, sodium-glucose linked transporter, glucose transporter, and l-type amino acid transporter) and transcriptional factors such as hepatocyte nuclear factor (HNF)4 alpha, sterol regulatory element-binding protein (SREBP)2, and liver X receptor (LXR)alpha were determined. In rats and mice fed an HC diet for 7 days, the mRNA and protein levels of NPC1L1 in the small intestine were determined by real-time reverse transcription polymerase chain reaction and western blotting, respectively. The mRNA levels of ABCG5 and ABCG8, six representative transporters, and transcriptional factors such as HNF4 alpha, SREBP2, and LXR were examined. Significant decreases in the expression levels of NPC1L1 were observed in mice, but not rats, fed the HC diet. The mRNA levels of ABCG5 and ABCG8 were significantly increased in HC rats but not in mice. Only minor changes in the mRNA levels of the other transporters were seen in HC rats and mice. Decreased mRNA levels of HNF4 alpha and SREBP2 in mice could be involved in the reduction in NPC1L1 expression observed upon the introduction of an HC diet. These results indicate that the effects of an HC diet on the expression levels of NPC1L1, ABCG5, and ABCG8 differ between mice and rats.
• Effects of dose, flow rate, and bile acid on diclofenac disposition in the perfused rat liver

  Misato Uraki; Atsushi Kawase; Yuka Matsushima; Masahiro Iwaki

  EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS SPRINGER FRANCE 41 (3) 301 - 307 0378-7966 2016/06 

  An in situ perfused rat liver system is useful for studying the hepatic disposition of drugs and their metabolites. However, the effects of the perfusion conditions on drug disposition are unclear. We examined the effects of conditions such as flow rate (13 or 26 mL/min) and bile acid on disposition of diclofenac (DF) as a model drug and DF metabolites [diclofenac-1-O-acyl glucuronide (DF-Glu) or 4'-hydroxydiclofenac (DF-4'OH)] in the absence of albumin. DF, DF-Glu, and DF-4'OH concentrations in the perfusate and cumulative amounts of DF-Glu excreted in bile were measured using high-performance liquid chromatography methods. DF in the perfusate was rapidly eliminated as the perfusate flow rate increased. The area under the plasma concentration-time curve from 0 to 60 min (AUC(0-60)) for DF-Glu and DF-4'OH in a perfusate containing bile acid was lower at a flow rate of 26 and 13 mL/min, respectively. The bile flow rate at 26 mL/min with 24 mu M of bile acid in the perfusate was significantly higher (ca. 3.5 times) compared with that at 13 mL/min without bile acid. Cumulative biliary DF-Glu excretion was also dramatically affected by the flow rate and addition of bile acid. This study indicated that the flow rate and bile acid in the perfused rat liver were key factors for bile flow rate and DF, DF-Glu, and DF-4'OH disposition in the absence of albumin.
• Stereoselective Inhibition of Methotrexate Excretion by Glucuronides of Nonsteroidal Anti-inflammatory Drugs via Multidrug Resistance Proteins 2 and 4

  Atsushi Kawase; Taiki Yamamoto; Sachiko Egashira; Masahiro Iwaki

  JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS 356 (2) 366 - 374 0022-3565 2016/02 

  Combined administration of methotrexate (MTX) and nonsteroidal anti-inflammatory drugs (NSAIDs) can result in a decreased systemic clearance of MTX. To date, inhibition of renal uptake via organic anion transporters and efflux via multidrug resistance-associated protein (MRPs) by NSAIDs has been recognized as possible sites of drug interaction between MTX and NSAIDs. Although most NSAIDs are glucuronidated in kidney tissue and excreted mainly as glucuronide conjugates, it is not fully known whether the glucuronides of NSAIDs (NSAIDs-Glu) inhibit MTX excretion via MRP2 and MRP4. The purpose of this study was to investigate the inhibitory effects of the glucuronides of several NSAIDs (diclofenac, R-and S-ibuprofen, R- and S-flurbiprofen, and R- and S-naproxen), as well as the parent NSAIDs on MTX uptake using human MRP2- and MRP4-expressing inside-out vesicles. Results confirm that all NSAIDs and NSAIDs-Glu examined exhibited stereoselective and concentration dependent inhibitory effects on MTX uptake via MRP2 and MRP4. Notably, NSAIDs-Glu potently inhibited MTX uptake via MRP2 and MRP4 compared with the corresponding parent NSAIDs except for naproxen in MRP2 and S-flurbiprofen in MRP4. The present results support that the glucuronides of NSAIDs, as well as the parent NSAIDs, are involved
• Effects of fasting on pravastatin disposition in perfused rat liver

  Atsushi Kawase; Ayumi Handa; Masahiro Iwaki

  International Journal of Pharmacy and Pharmaceutical Sciences Innovare Academics Sciences Pvt. Ltd 8 (12) 130 - 134 0975-1491 2016 

  Objective: Various nutrients such as glucose and cholesterol affect the expression of hepatic transporters. Although the pharmacokinetics of some drugs is affected by fasting, the fasting effects on drug hepatic disposition via alterations in transporters are unclear. Organic anion-transporting polypeptides and multidrug resistance-associated protein 2 (Mrp2/Abcc2) expressed in the liver are involved in hepatic disposition of pravastatin. Methods: An in situ perfused rat liver system was established. The mRNA and protein levels of transporters in the liver were examined by real-time reverse transcription PCR and western blotting. The localization of Mrp2 in hepatocytes was determined by immunostaining. Results: Pravastatin was rapidly eliminated from the perfusate. The cumulative biliary excretion amounts of pravastatin in fasting rats were significantly lower from 10 min compared with control. In fasting rats, the area under the plasma concentration-time curve (AUC)0‒∞ of pravastatin in the perfusate was significantly decreased, and hepatic clearance (CLh) and hepatic corrected clearance (CLcor) were significantly increased. The biliary clearance (CLbile) in fasting rats tended to decrease compared with that in control rats. Protein expression levels of transporters were unchanged after fasting. Confocal microscopy revealed a disruption of Mrp2 and ZO-1 colocalization in the liver of fasting rats. Conclusion: The biliary excretion of pravastatin was inhibited by fasting via decreased Mrp2 localization on the canalicular membrane.
• ALTERATIONS IN EXPRESSION AND FUNCTION OF EZIRIN/RADIXIN/MOESIN PROTEINS FOR TRANSPORTERS IN ADJUVANT-INDUCED ARTHRITIS RATS

  Iwaki Masahiro; Kawase Atsushi; Sakata Misato; Nakasaka Misaki; Kato Yukio

  DRUG METABOLISM REVIEWS 47 275  0360-2532 2015/11 [Refereed]
  
• Age-related changes in mRNA levels of hepatic transporters, cytochrome P450 and UDP-glucuronosyltransferase in female rats

  Atsushi Kawase; Ayami Ito; Ayano Yamada; Masahiro Iwaki

  EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS SPRINGER FRANCE 40 (2) 239 - 244 0378-7966 2015/06 

  Hepatic transporters and metabolic enzymes affect drug pharmacokinetics. Limited information exists on the alteration in mRNA levels of hepatic transporters and metabolic enzymes with aging. We examined the effects of aging on the mRNA levels of representative hepatic drug transporters and metabolic enzymes by analyzing their levels in 10-, 30- and 50-week-old male and female rats. Levels of mRNA of drug transporters including multidrug resistance protein (Mdr)1a, multidrug resistance-associated protein (Mrp)2, breast cancer resistance protein (Bcrp) and organic anion-transporting polypeptide (Oatp)1a1, and the metabolic enzymes cytochrome P450 (CYP)3A1, CYP3A2 and UDP-glucuronosyltransferase (UGT)1A1 were analyzed using real-time reverse transcriptase polymerase chain reaction. The mRNA levels of transporters in male rats did not decrease with age, while the mRNA levels of Bcrp and Oatp1a1 in female rats decreased with age. The mRNA levels of CYP3A1 and CYP3A2 in male rats were higher than those in female rats. The mRNA levels of metabolic enzymes decreased with age in female but not male rats. In particular, the mRNA levels of UGT1A1 in 10-week-old female rats were higher than those in male rats. mRNA expression of hepatic transporters and metabolic enzymes are more susceptible to aging in female than male rats. The age-related decreases in the mRNA levels of Bcrp, Oatp1a1, CYP3A1 and CYP3A2 in female rats may affect the metabolism and transport of substrates. This study showed that aging affected the mRNA expression of hepatic transporters and metabolic enzymes in rats.
• Pravastatin Modulate Niemann-Pick C1-Like 1 and ATP-Binding Cassette G5 and G8 to Influence Intestinal Cholesterol Absorption

  Atsushi Kawase; Seiji Hata; Mai Takagi; Masahiro Iwaki

  JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES CANADIAN SOC PHARMACEUTICAL SCIENCES 18 (5) 765 - 772 1482-1826 2015 

  Purpose. Niemann-Pick C1-like 1 (NPC1L1), ATP-binding cassette (ABC)G5, and ABCG8 mediate intestinal cholesterol absorption. It is unclear whether pravastatin (PR) or ezetimibe (EZ) affect expression of these transporters. We examined the effects of PR and EZ on NPC1L1, ABCG5, and ABCG8 expression in human hepatoma HepG2 cells and the murine small intestine. We also assessed expression of the transcription factors liver X receptor (LXR)alpha, LXR beta and sterol regulatory element-binding protein. Methods. Transporter mRNA levels were determined in murine small intestines 6 and 24 h after oral PR and EZ administration by real-time reverse-transcriptase polymerase chain reaction (RT-PCR). In PR-and EZ-treated HepG2 cells, transporter and transcription factor mRNA and protein levels were examined by RT-PCR and western blot, respectively. Results. Significant decreases in NPC1L1, ABCG5, and ABCG8 mRNA expression were observed in the duodenum, but not jejunum and ileum, of mice 24 h after treatment with PR, but not EZ. In HepG2 cells, PR but not EZ treatment for 24 h also significantly decreased NPC1L1 protein and ABCG5, and ABCG8 mRNA expression, while increasing LXR alpha mRNA levels. Conclusion. PR but not EZ treatment reduced duodenal cholesterol transporter expression in mice. PR-induced increases in LXR alpha mRNA levels may be involved in attenuation of NPC1L1 expression, subsequently decreasing intestinal cholesterol absorption.
• Decreased Radixin Function for ATP-Binding Cassette Transporters in Liver in Adjuvant-Induced Arthritis Rats

  Atsushi Kawase; Misato Sakata; Nagisa Yada; Misaki Nakasaka; Takuya Shimizu; Yukio Kato; Masahiro Iwaki

  JOURNAL OF PHARMACEUTICAL SCIENCES WILEY-BLACKWELL 103 (12) 4058 - 4065 0022-3549 2014/12 

  Pathophysiological changes are associated with alterations in the expression and function of numerous ADME-related proteins. We have previously demonstrated that the membrane localization of ATP-binding cassette (ABC) transporters in liver was decreased without change of total expression levels in adjuvant-induced arthritis (AA) in rats. Ezrin/radixin/moesin (ERM) proteins are involved in localization of some ABC transporters in canalicular membrane. The mRNA levels of radixin decreased significantly in liver but not kidney, small intestine, and brain. The mRNA levels of ezrin and moesin did not change in AA. The membrane localization of radixin was reduced in liver of AA and the ratios of activated radixin (p-radixin) to total radixin were decreased in AA, although the protein levels of radixin did not change in homogenate and membrane protein. To clarify whether AA affects the linker functions of ERM proteins, we examined the interactions between ERM proteins and ABC transporters. The interactions between radixin and ABC transporters were decreased in AA. In vitro studies using human hepatoma HepG2 cells showed that interleukin-1 decreased the mRNA levels of radixin and colocalization of radixin and Mrp2. Our results show that the decreased radixin functions affect the interaction between radixin and ABC transporters in inflammation. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:4058-4065, 2014
• Alterations in Expression and Function of ABC Transporters and ERM Proteins in Inflammation

  Atsushi Kawase

  YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 134 (9) 925 - 929 0031-6903 2014/09 

  Pathophysiological changes in infection or inflammation are associated with alterations in the production of numerous absorption-, distribution-, metabolism-, and excretion-related proteins. However, little information is available on the effects of inflammation on the expression levels and activities of ATP-binding cassette (ABC) transporters. We examined the effects of acute (on day 7) and chronic (on day 21) inflammation on the expression of ABC transporters in some major tissues in rats. Adjuvant-induced arthritis (AA) in rats was used as an animal model of inflammation. The mRNA levels of mdr1a and mdr1b encoding P-glycoprotein (P-gp) decreased significantly in the liver of AA rats on day 21. Hepatic protein levels of P-gp, Mrp2, and Bcrp decreased significantly in the membrane but not in the homogenate of AA rats after 7 days and after 21 days of treatment with adjuvant. Recently, ezrin/radixin/moesin (ERM) proteins have been found to show linker activity for some transporters and F-actin. We examined the expression levels and functions of ERM proteins in AA because the membrane localization of ABC transporters was decreased without any change in total expression levels. In this review, we summarize our recent work and reports of ERM proteins relevant to ABC transporters.
• Distinct Alterations in ATP-Binding Cassette Transporter Expression in Liver, Kidney, Small Intestine, and Brain in Adjuvant-Induced Arthritic Rats

  Atsushi Kawase; Sari Norikane; Ayaka Okada; Mamiko Adachi; Yukio Kato; Masahiro Iwaki

  JOURNAL OF PHARMACEUTICAL SCIENCES WILEY-BLACKWELL 103 (8) 2556 - 2564 0022-3549 2014/08 

  Pathophysiological changes of infection or inflammation are associated with alterations in the production of numerous absorption, distribution, metabolism and excretion-related proteins. However, little information is available on the effects of inflammation on the expression levels and activities of ATP-binding cassette (ABC) transporters. We examined the effect of acute (on day 7) and chronic (on day 21) inflammation on the expression of ABC transporters in some major tissues in rat. Adjuvant-induced arthritis (AA) in rats was used as an animal model for inflammation. The mRNA levels of mdr1a and mdr1b encoding P-glycoprotein (P-gp) decreased significantly in livers of AA rats on day 21. Hepatic protein levels of P-gp, Mrp2, and Bcrp decreased significantly in membranes but not homogenates of AA rats after 7 days and after 21 days of treatment with adjuvant. Contrary to liver, protein levels of P-gp and Mrp2, but not Bcrp in kidney, increased significantly in membranes. The biliary excretion of rhodamine 123 was decreased in rats with chronic inflammation owing to decreases in efflux activities of P-gp. Our results showed that the expression of transporters in response to inflammation was organ dependent. In particular, hepatic and renal P-gp and Mrp2 exhibited opposite changes in membrane protein levels. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2556-2564, 2014
• Effects of ginsenosides on the expression of cytochrome P450s and transporters involved in cholesterol metabolism

  Atsushi Kawase; Ayano Yamada; Yuko Gamou; Chika Tahara; Fumiaki Takeshita; Kazuya Murata; Hideaki Matsuda; Keiichi Samukawa; Masahiro Iwaki

  JOURNAL OF NATURAL MEDICINES SPRINGER JAPAN KK 68 (2) 395 - 401 1340-3443 2014/04 

  An extract from red ginseng (steamed and dried roots of Panax ginseng C.A. Meyer; RGE) has been shown to promote cholesterol metabolism in the liver. We have reported that RGE induced the hepatic expression of cytochrome P450 (CYP)7A1, involved in cholesterol metabolism. Other cholesterol metabolism-related proteins, such as CYP8B1, CYP27A1, multidrug resistance-associated protein (MRP)2, MRP3, and Na+ taurocholate cotransporting polypeptide (NTCP), are involved in cholesterol metabolism. The purpose of this study was to clarify whether RGE affected mRNA expression of cholesterol metabolism-related CYPs and transporters in the liver of hypercholesterolemic rats and rat primary hepatocytes. In-vivo studies showed little differences in CYP8B1, CYP27A1, MRP2, MRP3, and NTCP mRNA expression levels between hypercholesterolemic rats with or without RGE treatments. However, the disruption of the membrane localization of MRP2 was suppressed by RGE treatments in hypercholesterolemic rats. In-vitro studies using rat primary hepatocytes showed upregulation of CYP8B1 and MRP2 mRNA by the addition of RGE (100 and 500 mu g/mL). We further examined which ginsenosides contributed to the upregulation of CYP8B1 and MRP2 mRNA levels. Ginsenoside Re enhanced the mRNA level of CYP8B1, whereas ginsenosides Rb-2 and Rg(2) enhanced MRP2 mRNA levels. These results suggest that the in-vitro exposure of hepatocytes to RGE or some ginsenosides could lead to upregulation of CYP8B1 and MRP2, resulting in the alteration of biosynthesis and disposition of bile acids.
• Team-based Learning (TBL) in the Interdisciplinary Lecture

  Keiji Nishiwaki; Atsushi Kawase; Tetsuyuki Wada; Hideki Yagi; Naohito Kawasaki; Eiji Ito; Masahiro Iwaki

  YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 134 (2) 171 - 177 0031-6903 2014/02 

  We conducted team-based learning (TBL) with interdisciplinary lectures as a part of "Introduction to Pharmacy", divided among the pharmacy department's six pharmacist education curricula in the first semester. The interdisciplinary lecture is led by seven lecturers, each specializing in one area: cell biology, biochemistry, chemistry, public health pharmacology, pharmacokinetics, and clinical science. This lecture's purpose is to demonstrate to the students that all field subjects relate to each other and they must learn the basic science subjects to understand pharmaceutical sciences. The TBL contents have two themes, "cancer" and "aspirin", each of which had two lectures, each 90 minutes long and were conducted using TBL as expansive learning. On receiving knowledge of a wide range of fields in one lecture, a small number of students indicated that they were unable to understand the contents very well. However, in the questionnaire about TBL, many students reported "I have understood" and "I have enjoyed studying" using TBL, especially group readiness assessment test (GRAT). By incorporating TBL, they reported "increasing eagerness to learn pharmacy". Overall, students seem to have accepted TBL favorably, but they still find peer review difficult. We believe that their discomfort with peer review results from their unfamiliarity in evaluating others, and the time before the evaluation is short because TBL is conducted only twice.
• Increased effects of ginsenosides on the expression of cholesterol 7α-hydroxylase but not the bile salt export pump are involved in cholesterol metabolism

  Atsushi Kawase; Ayano Yamada; Yuko Gamou; Chika Tahara; Fumiaki Takeshita; Kazuya Murata; Hideaki Matsuda; Keiichi Samukawa; Masahiro Iwaki

  Journal of Natural Medicines 67 (3) 545 - 553 1340-3443 2013/07 

  An extract from red ginseng [steamed and dried roots of Panax ginseng C.A. Meyer (RGE)] has been shown to have various actions on physiological functions. The mechanisms by which RGE promotes cholesterol metabolism in the liver are unclear, but RGE decreases the plasma levels of cholesterol. We investigated whether RGE affected the mRNA expression of cholesterol metabolism-related proteins such as cytochrome P450 (CYP)7A1 and bile salt export pump (BSEP) in the liver in hypercholesterolemic rats and rat primary hepatocytes. In-vivo studies showed the upregulation of CYP7A1 mRNA in hypercholesterolemic rats treated with RGE. Treatment with RGE exhibited decreased ratios of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol compared with hypercholesterolemia without RGE. In-vitro studies also showed the upregulation of CYP7A1 mRNA and protein levels by the addition of RGE to rat primary hepatocytes. The mRNA levels of BSEP exhibited few changes. The sustained levels of the liver X receptor (LXR) in vivo and the increased levels of LXR in vitro on RGE treatment could be involved in the upregulation of CYP7A1. To clarify the effects of 11 ginsenosides including RGE on the mRNA levels of CYP7A1 and BSEP, we performed in-vitro experiments using rat primary hepatocytes. The ginsenosides Ro, Rg3, Re, Rg1, and Rg2 exhibited increased mRNA levels of CYP7A1. These results suggest that several ginsenosides including RGE promoted cholesterol metabolism due to upregulation of CYP7A1. © 2012 The Japanese Society of Pharmacognosy and Springer Japan.
• Alteration in plasma protein binding properties of propranolol and flurbiprofen during development of adjuvant-induced arthritis in rats

  Atsushi Kawase; Hiroyuki Ikuta; Satoshi Uno; Kana Yamamoto; Naomi Akitsu; Tomoaki Nagao; Masahiro Iwaki

  XENOBIOTICA INFORMA HEALTHCARE 43 (3) 246 - 252 0049-8254 2013/03 

  Adjuvant-induced arthritis (AA) in the rat is used as a model for rheumatoid arthritis. In AA rats, the pharmacokinetics of various drugs is affected due to the alterations of plasma protein binding of drugs. We choose propranolol (PL) and flurbiprofen (FP) as model basic and acidic drugs, respectively, and investigated the effect of AA induction on their plasma protein binding at each developing stage of inflammation. The plasma protein binding of PL and FP was dramatically changed due to reduced albumin and increased alpha(1)-acid glycoprotein levels for at least 21 days after adjuvant treatment. Moreover, we illustrated the differences in protein binding in AA between both the drugs in each developing stage of inflammation. These results suggest that the changed plasma protein levels in AA rats accompanying the altered protein binding of drugs affect the pharmacokinetics of drugs which extensively bind to plasma protein under inflammatory condition.
• Changes in mRNA Expression and Activity of Xenobiotic Metabolizing Enzymes in Livers from Adjuvant-induced Arthritis Rats

  Atsushi Kawase; Syoko Wada; Masahiro Iwaki

  Pharmacology & Pharmacy 4 478 - 483 2013
• Diurnal Variation of Nuclear Receptors in Mice with or without Fasting

  Atsushi Kawase; Tetsuya Ohgami; Iho Yoshida; Yu Tsunokuni; Masahiro Iwaki

  Pharmacology & Pharmacy 4 240 - 243 2013
• Strain Differences in the Induction of Cytochrome P450 3A1/3A2 and Nuclear Receptors in the Liver by Phenobarbital and Dexamethasone in Sprague-Dawley Rats and Dark Agouti Rats

  Atsushi Kawase; Toru Otori; Akiyuki Fujii; Ayano Yamada; Hiroshi Komura; Masahiro Iwaki

  JOURNAL OF HEALTH SCIENCE PHARMACEUTICAL SOC JAPAN 57 (5) 414 - 419 1344-9702 2011/10 

  Strain differences in the induction of cytochrome P450 (CYP) affect drug actions and side effects. Strain differences in the induction of CYP are important to evaluate drug-drug interactions in CYPs. We clarified strain differences in the induction of CYP3A1/3A2 and nuclear receptors by evaluating mRNA levels and metabolic activities in Sprague-Dawley (SD) rats and Dark Agouti (DA) rats (models for extensive and poor metabolism of CYP2D6, respectively). To clarify strain differences in CYP levels, we examined nuclear receptors such as the constitutive androstane receptor (CAR) and pregnane X receptor, which regulate the transcription of CYPs and transporters. We investigated CYP3A inductions in the liver after repeated intraperitoneal injections of phenobarbital (PB) or dexamethasone (DEX) into SD rats and DA rats for 3d. mRNA levels of CYP and nuclear receptors were determined by real-time reverse transcriptase-polymerase chain reaction. Metabolic activities of CYP3A were also determined. Increased CYP3A mRNA levels were observed in both rat strains after treatment with PB or DEX compared with the respective rat strains treated with vehicle alone. Induction of CYP3A mRNAs by DEX was higher in SD rats than in DA rats, suggesting that SD rats could be more susceptible to DEX than DA rats. Inductions of CAR by PB differed between strains. The increase in mRNA levels and activity of CYP3A by PB in SD rats and DA rats were similar. However, there were strain differences in CYP3A1/3A2 inductions after DEX treatment.
• Enhanced Safety Profiles of the Telomerase-Specific Replication-Competent Adenovirus by Incorporation of Normal Cell-Specific microRNA-Targeted Sequences

  Kumiko Sugio; Fuminori Sakurai; Kazufumi Katayama; Katsuhisa Tashiro; Hayato Matsui; Kenji Kawabata; Atsushi Kawase; Masahiro Iwaki; Takao Hayakawa; Toshiyoshi Fujiwara; Hiroyuki Mizuguchi

  CLINICAL CANCER RESEARCH AMER ASSOC CANCER RESEARCH 17 (9) 2807 - 2818 1078-0432 2011/05 

  Purpose: Oncolytic adenoviruses (Ad) have been actively pursued as potential agents for cancer treatment. Among the various types of oncolytic Ads, the telomerase-specific replication-competent Ad (TRAD), which possesses an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, has shown promising results in human clinical trials; however, the E1 gene is also slightly expressed in normal cells, leading to replication of TRAD and cellular toxicity in normal cells. Experimental Design: To overcome this problem, we utilized a microRNA (miRNA)-regulated gene expression system. Four copies of complementary sequences for miR-143, -145, -199a, or let-7a, which have been reported to be exclusively downregulated in tumor cells, were incorporated into the 3'-untranslated region of the E1 gene expression cassette. Results: Among the TRAD variants (herein called TRADs) constructed, TRADs containing the sequences complementary to miR-143, -145, or -199a showed efficient oncolytic activity comparable to the parental TRAD in the tumor cells. On the other hand, replication of the TRADs containing the miRNA complementary sequences was at most 1,000-fold suppressed in the normal cells, including primary normal cells. In addition, to suppress the replication of the TRADs in hepatocytes as well as other normal cells, we constructed a TRAD containing 2 distinct complementary sequences for miR-199a and liver-specific miR-122a (TRAD-122a/199aT). TRAD-122a/199aT exhibited more than 10-fold reduction in viral replication in all the normal cells examined, including primary hepatocytes. Conclusions: This study showed that oncolytic Ads containing the sequences complementary to normal cell-specific miRNAs showed significantly improved safety profiles without altering tumor cell lysis activity. Clin Cancer Res; 17(9); 2807-18. (C)2011 AACR.
• A Trial of the Integrated Cross-field Pharmaceutical Education in the First Year of Faculty of Pharmacy

  Tomohisa Yasuhara; Naohito Kawasaki; Hideki Yagi; Eiji Itoh; Atsushi Kawase; Toru Otori; Tetsuyuki Wada; Kenji Matsuyama; Masahiro Iwaki

  YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 130 (12) 1647 - 1653 0031-6903 2010/12 

  The six-year pharmacist education course has begun, and now first-year students receive clinical training. Interdisciplinary problem-solving capabilities covering chemistry, biology, molecular biology, pharmacology, pathology, and pharmacokinetics are necessary for new pharmacists. However, the conventional pharmaceutical science education was so separate from other fields that education for interdisciplinary cooperative capability was insufficient. This was especially true of elemental science courses, because they are not directly connected with clinical knowledge, and there is a problem of low student interest in those courses. As a result, students acquired only recall-level knowledge in clinical courses and their problem-solving capabilities in clinical treatment and drug development deteriorated. Therefore we offered a trial lecture aimed to help students recognize the important relationship between elemental science courses and clinical courses and increase their motivation to enroll in these courses. Specifically, the trial lecture covered cancer therapy, in reference to mechanisms of carcinogenesis, epidemiology, physiology of cancer, anticancer drugs with explanations of the mechanism of action of carcinogens, anticancer drugs, and molecular-targeted drugs from the viewpoints of organic chemistry and biochemistry by a specialized teacher. This paper reports on this experimental lecture with evaluations from students.
• Inhibitory Effects of Phytoncide Solution on Melanin Biosynthesis

  Hiroaki Fujimori; Masayoshi Hisama; Hiroharu Shibayama; Atsushi Kawase; Masahiro Iwaki

  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY TAYLOR & FRANCIS LTD 74 (5) 918 - 922 0916-8451 2010/05 

  To determine the component-activity relationships of phytoncide solutions on inhibitory activity in melanin biosynthesis, four types of phytoncide solution (A-type, AB-type, D-type, and G-type) were evaluated for inhibition of mushroom tyrosinase activity and melanin synthesis on murine B-16 melanoma cells and a human reconstituted skin model. The A-type, AB-type, D-type, and G-type of phytoncide solution treatment resulted in significant inhibition of tyrosinase activity. The amount of melanin was increased by treatment with phytoncide solutions in a concentration-dependent manner on murine B-16 melanoma cells without affecting cell growth. Furthermore, phytoncide solutions also suppressed melanin synthesis in a concentration-dependent manner on a human reconstituted skin model. These effects of A-type solution were superior to those of other solutions.
• Ginseng Extracts Facilitate Cytochrome P450 Xenobiotic Metabolism in Primary Cultures of Rat Hepatocytes

  Atsushi Kawase; Fumiaki Takeshita; Ayano Yamada; Kazuya Murata; Hideaki Matsuda; Keiichi Samukawa; Masahiro Iwaki

  JOURNAL OF HEALTH SCIENCE PHARMACEUTICAL SOC JAPAN 55 (5) 809 - 813 1344-9702 2009/10 

  A 70% methanol extract from red ginseng (steamed and dried roots of Panax ginseng C. A. Meyer, a kind of Ginseng Radix) has been shown to have various actions on physiological functions. We investigated whether the ginseng extract (Ext.) affected the mRNA expression of cytochrome P450 (CYP) CYP1A1, 2B1, 2C11, 2D1, 3A1, and 3A2 in rat primary hepatocytes. After treatment with ginseng extract, the levels of CYP3A1 and 1A1 mRNA were significantly increased compared with those of the control. The increased protein levels of CYP3A1 were also observed after treatment with Ext. The mRNA levels of other examined CYPs exhibited little change. The mRNA levels of the pregnane X receptor, but not the constitutive androstane receptor, both transcription factors for CYPs, also significantly increased after treatment with ginseng extract. These results raise the possibility that ginseng Ext. promotes xenobiotic metabolism via an increase in CYP3A1. and 1A1 expression.
• Enhanced CTL response by controlled intracellular trafficking of antigen in dendritic cells following DNA vaccination

  Keiko Isaji; Atsushi Kawase; Mitsuhiro Matono; Xin Guan; Makiya Nishikawa; Yoshinobu Takakura

  JOURNAL OF CONTROLLED RELEASE ELSEVIER SCIENCE BV 135 (3) 227 - 233 0168-3659 2009/05 

  To elicit a cytotoxic T lymphocytes (CTL) response efficiently after DNA vaccination, we constructed several plasmid DNA (pDNA) vectors encoding the major histocompatibility complex (MHC) class I-restricted epitope peptide (SIINFEKL) of ovalbumin (OVA) or OVA protein with modified intracellular trafficking. An in vitro antigen presentation assay was carried out using DC2.4 cells, a dendritic cell line, to examine the potentials of the constructs following direct transfection. Among the vectors, pPep-ER, pDNA encoding antigen peptide combined with an endoplasmic reticulum (ER)-retention signal, exhibited a significant ability of antigen presentation compared with the counterpart without the signal. Based on the in vitro results, we carried out in vivo immunization experiments using pPep-ER via the intradermal or intramuscular route in combination with electroporation in mice. pPep-ER showed an efficient antigen-specific CTL induction and the effect was superior to that exhibited by the positive control, OVA in complete Freund's adjuvant (CFA). The levels of interferon gamma (IFN-gamma) released from spleen cells were significantly increased by pPep-ER compared with pPep-free. Immunization with pPep-ER also exhibited a high inhibitory effect on the growth of E.G7 tumor. These results indicate that DNA vaccination with the pDNA vector expressing a MHC class I epitope peptide with controlled intracellular trafficking is a promising method of inducing an antigen-specific CTL response via direct presentation. (c) 2009 Elsevier B.V. All rights reserved.
• Differential Effects of Chrysin on Nitrofurantoin Pharmacokinetics Mediated by Intestinal Breast Cancer Resistance Protein in Rats and Mice

  Atsushi Kawase; Yukako Matsumoto; Motoshi Hadano; Yui Ishii; Masahiro Iwaki

  JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES CANADIAN SOC PHARMACEUTICAL SCIENCES 12 (2) 150 - 163 1482-1826 2009 

  Purpose. The activities of breast cancer resistance protein (Bcrp/ABCG2) as well as P-glycoprotein (P-gp) and drug-metabolizing enzymes can be inhibited by several flavonoids or drugs in rats. However, the species, sex and regional differences of effects of flavonoids on Bcrp/ABCG2 in rats and mice remain unclear, although Bcrp, like P-gp, is also important in controlling drug absorption and disposition. Methods. We used chrysin as a model flavonoid because it possesses anti-inflammatory and antioxidative properties and is used as a dietary supplement. We examined the pharmacokinetics of nitrofurantoin, a specific Bcrp substrate, after oral or intravenous administration in rats and mice treated with chrysin. Bcrp mRNA levels were measured in liver, kidney, duodenum, jejunum and ileum in rats and mice. Results. Oral chrysin increased plasma concentrations of nitrofurantoin in rats but not mice. Intraperitoneal injection of chrysin into rats or mice had little effect on the elimination of nitrofurantoin. The AUC(0-t) in female mice was 1.5-2.0 folds higher than in male mice after oral and intravenous administration of nitrofurantoin. Absorption of nitrofurantoin from apical to basal sides was significantly increased by chrysin in both duodenum and jejunum as well as in ileum in rat small intestine. Conclusions. Chrysin-nitrofurantoin interactions it takes place in the small intestine and occur in rats, but not in mice, possibly due to the higher levels of Bcrp in the small intestine in rats as compared with mice.
• Changes in mRNA Expression of ABC and SLC Transporters in Liver and Intestines of the Adjuvant-induced Arthritis Rat

  Satoshi Uno; Misato Uraki; Ayami Ito; Yuki Shinozaki; Ayano Yamada; Atsushi Kawase; Masahiro Iwaki

  BIOPHARMACEUTICS & DRUG DISPOSITION JOHN WILEY & SONS LTD 30 (1) 49 - 54 0142-2782 2009/01 

  In this study, a real-time reverse transcription-polymerase chain reaction was used to determine the effects of adjuvant-induced arthritis (AA) on the amounts of mRNA of 12 types of rat ATP-binding cassette (ABC) and solute carrier (SLC) transporters in the liver and small intestine, 7 (D7) and 21 days (D21) after the injection of adjuvant. There were no significant differences in mRNA levels of ABC and SLC transporters between the livers of AA and control rats on D7, except in the case of Mdr1a. However, levels of Mdr1a, Mrp2 and Cap SLC transporters were significantly lower in AA than in the control livers on D21. In contrast, the mRNA levels of several ABC and SLC transporters, especially Mrp2, Bcrp, LAT2 and Oatp1a5, were significantly lower in the small intestines of AA rats compared with the controls on D7, though there were no significant differences by D21. The time-dependent alterations in mRNA levels of the pregnane X receptor, but not the constitutive androstane receptor, in the liver and intestine were similar to the changes in mRNA levels of most transporters examined. The present study showed that AA was associated with reduced mRNA expression of several ABC and SLC transporters in the liver and small intestine, but that the time courses of the effects of AA on mRNA expression differed between the liver and small intestine. These results raise the possibility of a functional change of the transporters of liver and intestine in AA rats. Copyright (C) 2009 John Wiley & Sons, Ltd.
• Comparative evaluation of 12 immature citrus fruit extracts for the inhibition of cytochrome p450 isoform activities

  Tadashi Fujita; Atsushi Kawase; Toshiro Niwa; Norimichi Tomohiro; Megumi Masuda; Hideaki Matsuda; Masahiro Iwaki

  BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 31 (5) 925 - 930 0918-6158 2008/05 

  In a previous study we found that 50% ethanol extracts of immature fruits of Citrus unshiu (satsuma mandarin) have anti-allergic effects against the Type I, II and IV allergic reactions. However, many adverse interactions between citrus fruit, especially grapefruit juice, and drugs have been reported due to the inhibition of cytochrome P450 (CYP) activities. The purpose of this study was to examine the competitive inhibitory effects of extracts from immature citrus fruit on CYP activity. Extracts were prepared from 12 citrus species or cultivars, and were tested against three kinds of major CYPs, CYP2C9, CYP2D6 and CYP3A4, in human liver microsomes. We also estimated the amounts of flavonoids (narirutin, hesperidin, naringin and neohesperidin) and furanocoumarins (bergapten, 6',7'-dihydroxybergamottin and bergamottin) in each extract using HPLC. Citrus paradisi (grapefruit) showed the greatest inhibition of CYP activities, while Citrus unshiu which has an antiallergic effect, showed relatively weak inhibitory effects. Extracts having relatively strong inhibitory effects for CYP3A4 tended to contain higher amounts of naringin, bergamottin and 6',7'-dihvdroxybergamottin. These results, providing comparative information on the inhibitory effects of citrus extracts on CYP isoforms, suggest that citrus extracts containing high levels of narirutin and hesperidin and lower levels of furanocoumarins such as C. unshiu are favorable as antiallergic functional ingredients.
• Effect of a novel ascorbic derivative, disodium isostearyl 2-O-L-ascorbyl phosphate, on normal human dermal fibroblasts against reactive oxygen species

  Hiroharu Shibayama; Masayoshi Hisama; Sanae Matsuda; Atsushi Kawase; Mamitaro Ohtsuki; Katsumi Hanada; Masahiro Twaki

  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY TAYLOR & FRANCIS LTD 72 (4) 1015 - 1022 0916-8451 2008/04 

  The novel amphiphilic vitamin C derivative disodium isostearyl 2-O-L-ascorbyl phosphate (VCP-IS-2Na), which has a C-18 alkyl chain attached to the stable ascorbate derivative sodium L-ascorbic acid 2-phosphate (VCP-Na), was evaluated for reduction of cell damage induced by oxidative stress, ultraviolet A (UVA), ultraviolet B (UVB), and H2O2; stimulation of collagen synthesis against UVA irradiation; and inhibition of matrix metalloproteinase-1 (MMP-1) activity induced by UVA in human normal dermal fibroblasts. VCP-IS-2Na pretreatment resulted in significant protection against cell damage induced by UVB, UVA, and H2O2. The amount of type I collagen following UVA irradiation was increased by treatment with VCP-IS-2Na in a concentration-dependent manner. These effects of VCP-IS-2Na were superior to those Of L-ascorbic acid (vitamin C, VC) and VCP-Na. On the other hand, VCP-IS-2Na suppressed 65% of the excess MMP-1 irradiated UVA, and VC and VCP-Na slightly suppressed it.
• Anti-allergic effect of a combination of Citrus unshiu unripe fruits extract and prednisolone on picryl chloride-induced contact dermatitis in mice

  Tadashi Fujita; Takehumi Shiura; Megumi Masuda; Masashi Tokunaga; Atsushi Kawase; Masahiro Iwaki; Takeshi Gato; Masahiko Fumuro; Katsuaki Sasaki; Naoki Utsunomiya; Hideaki Matsuda

  JOURNAL OF NATURAL MEDICINES SPRINGER TOKYO 62 (2) 202 - 206 1340-3443 2008/04 

  Effect of 50% ethanolic extract of unripe fruits of Citrus unshiu (CU-ext) on type IV allergic reaction was examined by inhibitory activity of ear swelling of picryl chloride-induced contact dermatitis (PC-CD) in mice. Oral administration of CU-ext and subcutaneous administration of prednisolone showed inhibition of ear swelling during both induction and effector phases of PC-CD. The inhibitory activities of combinations of CU-ext (p.o.) and prednisolone (s.c.) during induction phase of PC-CD were more potent than those of CU-ext alone and prednisolone alone. Successive oral administration of hesperidin, a major flavanone glycoside of CU-ext, inhibited ear swelling during induction phase of PC-CD. The inhibitory activities of combinations of hesperidin (p.o.) and prednisolone (s.c.) were more potent than those of hesperidin alone and prednisolone alone. These results indicated that the combinations of prednisolone and CU-ext or hesperidin exerted a synergistic effect.
• ALTERATION ON THE MRNA EXPRESSION OF ABC AND SLC TRANSPORTERS IN LIVER AND INTESTINE OF ADJUVANT-INDUCED ARTHRITIS RAT

  Iwaki Masahiro; Uno Satoshi; Kawase Atsushi

  DRUG METABOLISM REVIEWS 40 213 - 214 0360-2532 2008 [Refereed]
  
• Impaired intrinsic chiral inversion activity of ibuprofen in rats with adjuvant-induced arthritis

  S. Uno; M. Uraki; H. Komura; H. Ikuta; A. Kawase; M. Iwaki

  XENOBIOTICA INFORMA HEALTHCARE 38 (11) 1410 - 1421 0049-8254 2008 

  1. The effects of adjuvant-induced arthritis on the chiral inversion of 'profens', a type of non-steroidal anti-inflammatory drug, have hardly been investigated. The authors investigated the effects of adjuvant-induced arthritis on the chiral inversion of ibuprofen using freshly isolated rat hepatocytes. 2. S- or R-ibuprofen was incubated with hepatocytes isolated from control and adjuvant-induced arthritis rats in the absence of the serum. In the hepatocyte system the chiral inversion rate constant of R- to S-ibuprofen and the metabolic rate constants of both enantiomers in adjuvant-induced arthritis rats were significantly decreased to about 64-80% of the corresponding values in control rats. In contrast, the addition of serum from each group to the corresponding hepatocyte medium resulted in no significant differences in these rate constants between control and adjuvant-induced arthritis rats. 3. With regard to chiral inversion enzymes, adjuvant-induced arthritis decreased the messenger RNA levels of acyl-coenzyme A synthetase (ACS) isoforms, but not 2-arylpropionyl-CoA epimerase, compared with control rats. 4. Chiral inversion of R- to S-ibuprofen was inhibited by triacsin C, a specific inhibitor of ACS1. 5. The results suggest that adjuvant-induced arthritis induces down-regulation of ACS enzymes involved in chiral inversion of R- to S-ibuprofen in rats.
• Prediction of metabolic clearance of diclofenac in adjuvant-induced arthritis rats using a substrate depletion assay

  S. Uno; A. Fujii; H. Komura; A. Kawase; M. Iwaki

  XENOBIOTICA TAYLOR & FRANCIS LTD 38 (5) 482 - 495 0049-8254 2008 

  1.The purpose of this study was to evaluate drug clearance measured by the metabolic intrinsic clearance (CLint) in a substrate depletion assay in comparison with the in vivo clearance (CLtot) observed in adjuvant-induced arthritis (AA) rats. 2. After intravenous administration of diclofenac as a model drug, CLtot was 2.8-fold higher in AA rats than in control rats. In two different substrate depletion assays with liver microsomes for glucuronidation and hydroxylation, the CLint values for glucuronidation was significantly decreased in AA rats to 60% of the value in control rats, whereas the CLint values for hydroxylation were similar. The unbound fraction of diclofenac in plasma (fu, plasma) was significantly higher (2.8-fold) in AA rats than in control rats. 3. Hepatic clearance predicted from the CLint values for both biotransformation pathways and fu, plasma was higher in AA rats than in control rats, with good consistency between predicted and observed values. The same results were obtained for experiments using hepatocytes. 4. The plasma protein-binding activities, rather than metabolic clearance, in both types of rats would be a determining factor in the pharmacokinetic behaviour differences between control and AA rats. 5. In summary, substrate depletion assays with liver microsomes and hepatocytes in combination with protein binding assessment can help to predict changes in pharmacokinetics under AA conditions.
• Gastrointestinal Absorption of Hesperidin and Hesperetin after Oral Administration of Immature Citrus Unshiu Extract to Rats

  Tadashi Fujita; Atsushi Kawase; Nanae Nishijima; Megumi Masuda; Hideaki Matsuda; Masahiro Iwaki

  Shoyakugaku zasshi 日本生薬学会 62 (1) 8 - 14 1349-9114 2008 

  Hesperidin and hesperetin having an antiallergic effect are contained abundantly in immature fruit of Citrus unshiu. However, the gastrointestinal absorption of hesperidin and hesperetin as an aglycone of hesperidin after oral administration of Citrus unshiu extract (CU-ext) has not been clarified. We developed a simultaneous HPLC analysis for hesperidin and hesperetin in plasma and investigated the pharmacokinetics of hesperidin and hesperetin after oral administration of CU-ext compared with that after hesperidin solution or suspension in rats. Much higher plasma concentrations of hesperidin and hesperetin were observed after administration of CU-ext compared to those after hesperidin suspension. The maximum plasma concentration (Cmax) and bioavailability of hesperidin was 835 ng/mL and 3.5-7%, respectively, after administration of CU-ext (200 mg/kg), although respective values after hesperidin suspension were only 144 ng/mL and 0.5-1.5%. Comparison of the ratio of AUC o fhesperetin to that of hesperidin also demonstrated that a part of hesperidin was absorbed after conversion to hesperetin. This study showed that the form of CU-ext could promote the absorption of hesperidin.
• Differences in Cytochrome P450 and Nuclear Receptor mRNA Levels in Liver and Small Intestines between SD and DA Rats

  Atsushi Kawase; Akiyuki Fujii; Makiko Negoro; Ryosuke Akai; Miki Ishikubo; Hiroshi Komura; Masahiro Iwaki

  DRUG METABOLISM AND PHARMACOKINETICS JAP SOC STUDY XENOBIOTICS 23 (3) 196 - 206 1347-4367 2008 

  This study aimed to clarify the differences in mRNA levels of cytochrome P450 (CYP) isoforms and nuclear receptors between Dark Agouti (DA) and Sprague-Dawley (SD) rats which are animal models for poor metabolizers and extensive metabolizers for CYP2D6, respectively. Using liver and small intestine tissues of both rat strains, we investigated the mRNA levels of CYP1A, 2A, 2B, 2C, 2D, 2E, and 3A subfamilies and nuclear receptors which regulate the transcription of CYP isoforms. In the liver, male DA rats showed a low CYP2D2 mRNA level but high mRNA levels of CYP3A1, 3A2, and 1A1 compared to SD rats. No significant difference was noted in other CYP isoforms. The mRNA levels of CAR were higher in DA rats than those in SD rats. In small intestine, the mRNA levels of CYP isoforms and nuclear receptors exhibited no significant strain differences. In addition, the activity of CYP3A in small intestinal microsome did not differ between SD and DA rats. Female DA rats exhibited higher mRNA levels of CYP3A1, 3A2, and 2B1 in the liver than female SD rats. In conclusion, the mRNA levels of CYP3A1 and 3A2 isoforms and CAR in the liver but not in the small intestines were different between DA and SD rats in both sexes.
• Gum arabic enhances intestinal calcium absorption in rats

  Atsushi Kawase; Noriko Hirata; Masashi Tokunaga; Hideaki Matsuda; Masahiro Iwaki

  JOURNAL OF HEALTH SCIENCE PHARMACEUTICAL SOC JAPAN 53 (5) 622 - 624 1344-9702 2007/10 

  We investigated whether the efficiency of intestinal calcium (Ca) absorption was improved by concomitant ingestion of gum arabic (GA) in rats. We used the Ussing chamber method to clarify the effect of GA on upper and lower small intestinal absorption of Ca. Increased in vitro Ca permeation was observed in rats who ingested water with 7.5% GA for 10 days. These results suggested that administration of GA with Ca could increase the efficiency of oral Ca absorption.
• Effects of alterations in CAR on bilirubin detoxification in mouse collagen-induced arthritis

  Atsushi Kawase; You Tsunokuni; Masahiro Iwaki

  DRUG METABOLISM AND DISPOSITION AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS 35 (2) 256 - 261 0090-9556 2007/02 

  Nuclear receptors such as constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate the transcription of cytochromes P450 and transporters. We investigated whether quantitative and functional changes in CAR and PXR could affect bilirubin detoxification in chronic arthritis. The CAR mRNA level was significantly decreased in the liver of mice with collagen-induced arthritis (CIA) compared with control mice. In normal mice treated with CAR agonists, relatively rapid elimination of bilirubin was observed after its intravenous injection. Next, we investigated the effects of CAR on bilirubin-detoxifying enzymes and transporters in arthritis. The mRNA levels of organic anion transporter peptide (OATP) 2, glutathione S-transferase (GST) A1, and GSTA2 were decreased in CIA mice, whereas the mRNA levels of OATP4, UDP-glucuronosyltransferase 1A1, and multidrug resistance-associated protein 2 remained unchanged. The protein levels and transport activities of OATP2 were also decreased in CIA mice. Furthermore, the CIA mice actually exhibited retarded elimination of bilirubin after its intravenous injection. These results indicate that alterations to CAR during arthritis affect the elimination of bilirubin because of changes in multiple bilirubin-detoxifying enzymes and transporters.
• 塩酸デクスメデトミジンの体循環および肺循環に及ぼす影響

  稲森雅幸; 川瀬篤史; 岩城正宏; 古賀義久

  Med J Kinki Univ 近畿大学 32 (4) 243 - 251 0385-8367 2007 

  塩酸デクスメデトミジン(Dex)は,重症患者の鎮静に用いられるため,低酸素血症を誘発する可能性がないことを確かめておく必要がある.そこで,肺循環への作用を明確にする目的で,家兎循環動態標本ならびに肺動脈送血,左心房脱血の定流量再潅流標本を作成し,Dexの持続投与による全身の循環動態への影響およびHPV反応に及ぼす影響を検討した.また,心臓手術後の集中治療室入室患者に対し,Dex持続投与による循環動態の変化を検討した.Dexを全身麻酔下の家兎に投与したところ,平均動脈圧(MAP)は投与初期に低下したが,平均肺動脈圧(MPAP)は変化しなかった.心拍数(HR),心拍出量(CO)は投与後速やかに減少したが,一回拍出量(SV)の減少は認められなかった.血中濃度は投与後約60分で定常状態に達すると推測された.HPV反応はDex投与により増強も減弱もしなかった.しかし,臨床使用濃度の約400倍と考えられる高濃度では肺動脈圧の上昇が認められた.心臓手術後患者に初期負荷投与を行わずDexを持続投与したところ,初期負荷投与で生じる急激な高血圧,低血圧などの循環動態の変動は認められず,60分後には鎮静レベルも良好であった.Dexは早期開始により循環動態の変動を少なくすることができ,また,HPV反応に与える影響がないため,低酸素血症を引き起こす可能性は極めて少ないものと考えられた.
• Decreased intestinal CYP3A and p-glycoprotein activities in rats with adjuvant arthritis

  Satoshi Uno; Atsushi Kawase; Akiko Tsuji; Tadatoshi Tanino; Masahiro Iwaki

  DRUG METABOLISM AND PHARMACOKINETICS JAP SOC STUDY XENOBIOTICS 22 (4) 313 - 321 1347-4367 2007 

  Adjuvant- induced arthritis (AA) rats have been used as an animal model for rheumatoid arthritis. Several studies have shown that the pharmacokinetics of a number of drugs are altered in AA rats. We investigated the effects of AA on the barrier functions of the intestine using a rat model. Intestinal CYP3A activities (midazolam 1'-hydroxylation and 7-benzyloxy-4-(trifluoromethyl)-coumarin 7-hydroxylation) in AA rats were significantly decreased compared with those in normal rats, with marked decrease observed in the upper segment of intestine. Intestinal P-glycoprotein (P-gp) activitiy at upper segment was also significantly decreased in AA rats to 60% of that in normal rats, and the other segments (middle and lower) of intestine also exhibited tendencies toward decrease in P-gp activity. This decrease was supported by the finding that levels of mdr1a mRNA and P-gp protein were decreased in AA rats. No significant diSerences were observed in intestinal paracellular and transcellular permeability between AA and normal rats. These results suggest that intestinal CYP3A and P-gp activities are decreased in AA rats, and that the pharmacokinetics and bioavailabilities of drugs whose membrane permeation is limited by intestinal CYP3A and/or P-gp may be altered in rheumatic diseases.
• Decreased PXR and CAR inhibit transporter and CYP mRNA Levels in the liver and intestine of mice with collagen-induced arthritis

  A. Kawase; I. Yoshida; Y. Tsunokuni; M. Iwaki

  XENOBIOTICA TAYLOR & FRANCIS LTD 37 (4) 366 - 374 0049-8254 2007 

  Nuclear receptors, such as pregnane X receptor (PXR) and constitutive androstane receptor (CAR), regulate the transcription of transporters and cytochrome P450s (CYPs). We investigated whether quantitative and functional changes in PXR and CAR affected the transporters and CYPs in a mouse model of chronic arthritis. The mRNA levels of PXR were significantly decreased in the intestine of mice with collagen-induced arthritis (CIA) compared with control mice. The mRNA levels of CAR were significantly decreased in both the liver and intestine of CIA mice. The mRNA levels of Mdr1a/1b, Mrp3, BCRP and Cyp2b10 were decreased in the liver of CIA mice, while little change in the mRNA levels was observed for Cyp3a11 in the liver and the transporters in the intestine. Taken together, the present results reveal that the effects of CAR mRNA suppression on the regulation of transporters and CYPs differ between the liver and intestine in chronic arthritis.
• Enhanced antigen-specific antibody production following polyplex-based DNA vaccination via the intradermal route in mice

  Atsushi Kawase; Keiko Isaji; Ayumi Yamaoka; Naoki Kobayashi; Makiya Nishikawa; Yoshinobu Takakura

  VACCINE ELSEVIER SCI LTD 24 (27-28) 5535 - 5545 0264-410X 2006/07 

  DNA vaccination is an attractive approach with various advantages over conventional vaccination. The present study was undertaken to examine whether polyplex-based DNA vaccination could be used to modulate immune responses by plasmid DNA (pDNA). Methylated bovine serum albumin (mBSA) was used as a model of a cationic macromolecular carrier of pDNA encoding obalbumin (OVA) and the effects of polyplex formation of pDNA with mBSA on the antigen-specific immune responses were examined. Anti-OVA IgG antibody production was significantly increased following intradermal immunization with the polyplex compared with naked pDNA, although the induction of cytotoxic T lymphocyte activity was lowered by polyplex formation. We also demonstrated that the disposition and gene expression of pDNA following intradermal injection could be manipulated by polyplex formation. Intriguingly, we also found that the migration of dendritic cells to the injected site could be induced by polyplex formation probably due to a high level of tumor necrosis factor a production from the keratinocytes treated with mBSA/pDNA complexeses. Thus, the present study has demonstrated that the immune responses could be biased towards a Th2-type response by polyplex-based DNA vaccination through manipulation of not only pDNA disposition but also dendritic cell migration. (c) 2006 Elsevier Ltd. All rights reserved.
• EFFECT OF ALTERATION OF CAR ON BILIRUBIN DETOXIFICATION IN MICE COLLAGEN-INDUCED ARTHRITIS

  Kawase Atsushi; Tsunokuni You; Iwaki Masahiro

  Abstracts of Annual meeting of Japanese Society for the Study of Xenobiotics The Japanese Society for the Study of Xenobiotics 21 259 - 259 2006
• IN VITRO ALTERATION ON THE CHIRAL INVERSION OF IBUPROFEN IN ADJUVANT-INDUCED ARTHRITIS RAT HEPATOCYTES

  Uno Satoshi; Uraki Misato; Kawase Atsushi; Iwaki Masahiro

  Abstracts of Annual meeting of Japanese Society for the Study of Xenobiotics The Japanese Society for the Study of Xenobiotics 21 199 - 199 2006
• Application of substrate depletion assay for early prediction of nonlinear pharmacokinetics in drug discovery: Assessment of nonlinearity of metoprolol, timolol, and propranolol

  H Komura; A Kawase; M Iwaki

  JOURNAL OF PHARMACEUTICAL SCIENCES JOHN WILEY & SONS INC 94 (12) 2656 - 2666 0022-3549 2005/12 

  The purpose of this study was to investigate the advantages of the substrate depletion assay for evaluating linearity of pharmacokinetics compared with the metabolite formation assay. For propranolol, metoprolol, and nisoldipine with multiple and/or sequential metabolisms, the Michaelis constant (K-m) and maximum metabolic intrinsic clearance obtained from the depletion assay using rat and human liver microsomes showed a good correlation with relevant parameters with the formation assay. In vitro kinetics and in vivo pharmacokinetic profiles after oral administration of timolol, metoprolol, and propranolol, were investigated in rats using the depletion assay. The same rank order was found between nonlinearities based on dose-normalized areas under the plasma concentration curve (AUC/Dose) and K-m values. Using the kinetic parameters of these compounds, AUC was predicted based on a physiological based pharmacokinetic model incorporated saturable metabolism. The AUCs predicted for propranolol and metoprolol had a good relationship with those observed in the in vivo studies, implying that the depletion assay could be useful for assessing linearity of pharmacokinetics. (c) 2005 Wiley-Liss, Inc. and the American Pharmacists Association.
• Manipulation of local disposition and gene expression characteristics of plasmid DNA following intramuscular administration by complexation with cationic macromolecule

  A Kawase; N Kobayashi; K Isaji; M Nishikawa; Y Takakura

  INTERNATIONAL JOURNAL OF PHARMACEUTICS ELSEVIER SCIENCE BV 293 (1-2) 291 - 301 0378-5173 2005/04 

  To modulate the immune responses of DNA vaccine, it is very important to control the disposition and gene expression of plasmid DNA (pDNA) after local administration. We chose methylated bovine serum albumin (mBSA), a cationic macromolecule, as a carrier of pDNA. We examined the effects of complexation of pDNA with mBSA on the disposition and gene expression in mice after intramuscular administration. The elimination from injection site was retarded and the accumulation to lymph nodes was increased at the positively charged mBSA/pDNA complexes. As the charge ratios of mBSA/pDNA complexes were higher, the levels of gene expression were reduced. Antigen specific immune responses were evaluated using pDNA encoding ovalbumin (OVA), pCMV-OVA, as a model antigen-expressing pDNA. However, significant levels of production of anti-ovalbumin IgG antibody were obtained in mice immunized with a positively charged complex, mBSA/pCMV-OVA (8:1) (weight ratio). In vitro experiments using DC2.4 cells, a murine dendritic cell line, demonstrated that the levels of gene expression and cytokine release were increased by complexation. These results suggest that the immune responses might be manipulated by complexation presumably due to the altered disposition and gene expression of pDNA. (c) 2005 Elsevier B.V. All rights reserved.
• Hepatic delivery of particulates in the submicron range by a hydrodynamics-based procedure: implications for particulate gene delivery systems

  N Kobayashi; K Hirata; S Chen; A Kawase; M Nishikawa; Y Takakura

  JOURNAL OF GENE MEDICINE JOHN WILEY & SONS LTD 6 (4) 455 - 463 1099-498X 2004/04 

  Background A large-volume intravenous (i.v.) injection of DNA, i.e. a hydrodynamics-based transfection procedure, is known to be an efficient and liver-specific method of in vivo gene delivery. However, little is available on an applicable particle size in the procedure. Methods We examined the effect of particle size on the hepatic delivery by the hydrodynamics-based procedure, using fluorescein isothiocyanate labeled polystyrene microspheres (MS) of 50, 200 or 500 nm in diameter. MS were injected intravenously to mice by a conventional (normal) or the hydrodynamics-based procedure and their degree of hepatic uptake was determined fluorometrically. Results For all sizes tested, the two procedures were similar in terms of the apparent degree of hepatic uptake, whereas the intrahepatic localization of MS was apparently different between the procedures as shown by an examination of frozen tissue sections. In mice with gadolinium chloride induced Kupffer cell blockade, the hepatic uptake of MS following the normal procedure was decreased while that of the hydrodynamics-based procedure was less affected. This phenomenon of enhanced hepatic delivery seemed to be more effective for larger particles. Confocal microscopic observation of hepatocyte suspensions indicated that part of the injected MS-50 was delivered intracellularly following the hydrodynamics-based procedure, whereas almost all the observed MS-200 and MS-500 were detected in the extracellular compartment or on the surface of the cells. This was supported by the fact that most of the injected MS existed pericellularly around the transgene-expressing cells. Conclusions The hydrodynamics-based procedure facilitated extravasation and hepatic delivery of MS. Larger MS were more efficiently extravasated and trapped by the liver, whereas intracellular delivery hardly occurred with them. Copyright (C) 2004 John Wiley Sons, Ltd.
• Vector-based in vivo RNA interference: Dose- and time-dependent suppression of transgene expression

  N Kobayashi; Y Matsui; A Kawase; K Hirata; M Miyagishi; K Taira; M Nishikawa; Y Takakura

  JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS 308 (2) 688 - 693 0022-3565 2004/02 

  RNA interference (RNAi) induced by delivery of a small-interfering RNA (siRNA)-expressing vector was characterized in mice. siRNA-expressing plasmid DNA (pDNA) was injected by a hydrodynamics-based procedure along with pDNA encoding an exogenous target luciferase gene. A comparative study showed that stem-loop-type siRNA-expressing pDNA was superior, in terms of the transgene suppressive efficacy, to the tandem-type in the liver following systemic delivery of these pDNAs. Transgene suppression occurred in the liver, kidney, and lung as well as muscle. The degree of suppression was dependent on the dose of siRNA-expressing pDNA and the time at which transgene expression was determined following simultaneous injection of siRNA-expressing and target pDNAs. A reduction in transgene expression became apparent at 1 day after injection, whereas a lower degree of inhibition was obtained before this, as early as 6 h even in mice treated with an excess of siRNA-expressing pDNA. These results suggest that delivery of siRNA-expressing pDNA requires a period of time for induction of RNAi. A study of sequential injections revealed that prior injection of siRNA-expressing pDNA produced a significant suppression for at least 1 day, which disappeared within 4 days. Confocal microscopic studies indicated that the localization of the cells with successful delivery of transgene was different between primary and secondary hydrodynamics-based injections, accounting for the less effective inhibition following the sequential injections. Taken together, these results demonstrate that vector-based in vivo RNAi is a dose- and time-dependent process and offers the possibility of suppressing endogenous targets in a variety of somatic cells.
• Disposition and gene expression characteristics in solid tumors and skeletal muscle after direct injection of naked plasmid DNA in mice

  A Kawase; T Nomura; K Yasuda; N Kobayashi; M Hashida; Y Takakura

  JOURNAL OF PHARMACEUTICAL SCIENCES JOHN WILEY & SONS INC 92 (6) 1295 - 1304 0022-3549 2003/06 

  Previous studies have suggested that direct injection of naked plasmid DNA (pDNA) into solid tumors can be a useful method for in vivo gene transfer into tumor cells. To gain more insight into this approach, we studied the disposition and gene expression characteristics of naked pDNA after intratumoral injection by direct comparison with those after intramuscular injection in mice. pDNA encoding reporter genes were directly injected into subcutaneous solid tumor models and skeletal muscles. Biodistribution studies using radiolabeled pDNA showed that the elimination of pDNA from the injection site was relatively fast and a part of the pDNA was absorbed from the lymphatic system after both local injections. Confocal microscopic studies using fluorescein-labeled pDNA demonstrated that pDNA distributed efficiently throughout the muscle tissue whereas pDNA localization in the tumor tissue was restricted. Characterization of gene expression clarified the variation in expression level between tumor preparations and some factors affecting the expression level in the tumor. Reporter gene expression was significantly inhibited by simultaneous administration of some polyanions in both cases, suggesting that a specific mechanism may be involved in the naked pDNA uptake by muscle and tumor cells. These findings provide useful information for direct naked pDNA delivery into solid tumors. (C) 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm.

Conference Activities & Talks

• アセトアミノフェン誘発性肝障害に対するPGE2不活化酵素15-PGDH阻害の影響

  島田絋明; 横飛暉斗; 高田万桜; 川瀬篤史; 岩城正宏

  日本薬学会第143年会  2023
• 定型抗精神病薬pimozideの構造展開により開発した新規T型Ca2+チャネル阻害薬KTtp38: チャネル選択性, 電気生理学的特徴, 鎮痛活性の評価

  笠波嘉人; 高島康宏; 木野貴博; 石川千浩; 長南百香; 豊岡尚樹; 関口富美子; 坪田真帆; 川瀬篤史; 大久保つや子; 吉田 繁; 岡田卓哉; 川畑篤史

  第96回日本薬理学会年会  2022
• The regulation of hepatic prostaglandin E2 amount and its effect on acetaminophen-induced liver injury through improving endothelial damages

  横飛暉斗; 島田紘明; 吉川幸伽; 山本望乃花; 川瀬篤史; 岩城正宏

  日本薬物動態学会第37回年会  2022
• The Hydrolysis of Acyl Glucuronides in Human and Rat Liver Microsomes

  生田博之; 島田紘明; 阪本健次郎; 中村令奈; 川瀬篤史; 松野純男; 岩城正宏

  日本薬物動態学会第37回年会  2022
• Simultaneous quantification of eicosanoids produced in the liver S9 fractions

  島田紘明; 竹田祐佳; 川瀬篤史; 岩城正宏

  日本薬物動態学会第37回年会  2022
• アセトアミノフェン誘発性血管内皮傷害に対するプロスタグランジンE2の抑制作用

  山本望乃花; 島田紘明; 横飛暉斗; 川瀬篤史; 岩城正宏

  第72回日本薬学会関西支部総会・大会  2022
• HepG2細胞とTHP-1細胞由来マクロファージとの共培養におけるNSAIDsによる細胞傷害の変動

  柏木理佐; 川瀬篤史; 田中さつき; 高島桜花; 島田紘明; 岩城正宏

  第72回日本薬学会関西支部総会・大会  2022
• NSAIDsアシルグルクロニドのUGT1A9およびUGT2B7活性に対する影響

  湯山博司; 川瀬篤史; 岡祐里奈; 吉川真白; 吉里 翼; 島田紘明; 岩城正宏

  第72回日本薬学会関西支部総会・大会  2022
• 炎症モデルマウスにおけるGSH輸送トランスポーターSlc25a39/40の発現および機能変動

  畑中もも子; 川瀬篤史; 松田尚也; 首藤礼華; 島田紘明; 岩城正宏

  第72回日本薬学会関西支部総会・大会  2022
• 芳香族L-アミノ酸脱炭酸酵素を阻害しないD-carbidopaはH2S産生酵素cystathionine-β-synthaseを阻害することでTNBS誘起結腸痛を抑制する

  井場祐里子; 本夛泉侑; 坪田真帆; 川瀬篤史; 岡田卓哉; 豊岡尚樹; 川畑篤史

  第141回日本薬理学会近畿部会  2022
• 炎症モデルマウスにおけるグルタチオン輸送トランスポーターSlc25a39/40発現および機能変動

  川瀬篤史; 畑中もも子; 松田尚也; 首藤礼華; 島田紘明; 岩城正宏

  第49回日本毒性学会  2022
• ヒト肝ミクロソーム中におけるアシルグルクロン酸抱合体の加水分解特性

  島田紘明; 生田博之; 阪本健次郎; 中村令奈; 川瀬篤史; 松野純男; 岩城正宏

  日本薬剤学会第37年会  2022
• Ilex Latifolia葉抽出物の食後血統上昇抑制作用

  笹井剛一; 島田紘明; 上野省一; 川瀬篤史; 森川敏生; 岩城正宏

  日本薬学会第142年会  2022
• Acetaminophen誘発性肝障害に対する15-hydroxyprostaglandindehydrogenase阻害の影響

  横飛暉斗; 島田紘明; 吉川幸伽; 山本望乃花; 川瀬篤史; 岩城正宏

  日本薬学会第142年会  2022
• LPS投与による炎症モデルマウスにおける肝臓と腎臓のトランスポーター発現変動に対するHMGB1の役割

  松田尚也; 川瀬篤史; 入江浩太; 髙井柚希; 島田紘明; 岩城正宏

  日本薬学会第142年会  2022
• 肝ミクロソーム中における非ステロイド性抗炎症薬のアシルグルクロン酸抱合体の加水分解特性

  阪本健次郎; 島田紘明; 生田博之; 川瀬篤史; 岩城正宏

  日本薬学会第142年会  2022
• 芳香族Lアミノ酸脱炭酸酵素阻害薬カルビドパはH2S産生酵素cystathionine-β-synthaseを阻害することで内臓痛を抑制する

  井場祐里子; 本夛泉侑; 坪田真帆; 川瀬篤史; 岩城正宏; 川畑篤史

  第71回日本薬学会関西支部  2021
• 非ステロイド性抗炎症薬のアシルグルクロン酸抱合体のラットおよびヒト肝ミクロソーム中における加水分解

  生田博之; 島田紘明; 川瀬篤史; 岩城正宏

  第71回日本薬学会関西支部  2021
• 四塩化炭素およびアセトアミノフェン誘発性肝障害における肝プロスタグランジンE2量調節機構

  島田紘明; 横飛暉斗; 山田 爽; 川瀬篤史; 岩城正宏

  第71回日本薬学会関西支部  2021
• LPS誘発炎症モデルマウスの肝臓および腎臓におけるトランスポーター変動におけるHMGB1の役割

  髙井柚希; 川瀬篤史; 入江浩太; 松田尚也; 島田紘明; 岩城正宏

  第71回日本薬学会関西支部  2021
• NSAIDsアシルグルクロン酸抱合体と肝臓内タンパク質の共有結合体生成における立体選択性

  岡祐里奈; 川瀬篤史; 山下莉央; 吉里 翼; 吉川真白; 島田紘明; 岩城正宏

  第71回日本薬学会関西支部  2021
• Diclofenacによる細胞傷害に対するHepG2とTHP-1の接触型および非接触型共培養の影響

  田中さつき; 川瀬篤史; 高島桜花; 島田紘明; 岩城正宏

  第71回日本薬学会関西支部  2021
• NHERF1/EBP50を標的とした排出トランスポーターの機能調節

  川瀬篤史; 小山勇之介; 深江彩加; 首藤礼華; 島田紘明; 岩城正宏

  第71回日本薬学会関西支部  2021
• Acetaminophen誘発性肝障害におけるprostaglandin E2量調節機構とその役割

  横飛暉斗; 島田紘明; 吉川幸加; 川瀬篤史; 岩城正宏

  第63回日本脂質生化学会  2021
• LPSラットにおけるジフェンヒドラミン投与時の脳移行性の変動

  中馬泰平; 川瀬篤史; 入江浩太; 松田尚也; 覚野明日香; 島田紘明; 岩城正宏

  日本薬学会関西支部大会第70年会  2020
• NSAIDsアシルグルクロン酸抱合体のグルクロン酸転移酵素に対する立体選択的な共有結合体生成

  山下莉央; 川瀬篤史; 高島桜花; 吉里 翼; 島田紘明; 岩城正宏

  日本薬学会関西支部大会第70年会  2020
• Carbamazepine誘発性肝障害における肝prostaglandin E2量調節機構

  大場憲一; 島田紘明; 橋本凌汰; 川瀬篤史; 岩城正宏

  日本薬学会関西支部大会第70年会  2020
• Acetaminophen誘発性肝障害における肝Prostaglandin E2量調節機構とその意義

  横飛暉斗; 島田紘明; 吉川幸伽; 川瀬篤史; 岩城正宏

  日本薬学会関西支部大会第70年会  2020
• 薬物誘発性肝障害における肝プロスタグランジンE2量調節機構

  大場憲一; 島田紘明; 吉川幸伽; 山田 爽; 川瀬篤史; 岩城正宏

  第62回日本脂質生化学会  2020
• マウスにおけるシトクロムP450誘導過程におけるプロテインキナーゼNファミリーの役割

  川瀬篤史; 向井秀幸; 立石駿介; 黒田真太郎; 松田尚也; 佐藤亮介; 島田紘明; 杉浦麗子; 岩城正宏

  日本薬学会第140年会  2020
• In situ肝還流法によるジクロフェナクの肝毒性評価

  清水佑里子; 島田紘明; 藤原麻由; 川瀬篤史; 岩城正宏

  日本薬学会第140年会  2020
• Lipopolysaccharide投与ラットにおけるdiphenhydramine脳移行性の変動

  中馬泰平; 川瀬篤史; 入江浩太; 覚野明日香; 松田尚也; 島田紘明; 岩城正宏

  日本薬学会第140年会  2020
• 肝細胞とマクロファージの共培養系を用いたジクロフェナク誘発性細胞傷害の評価

  山下莉央; 川瀬篤史; 高島桜花; 吉里 翼; 島田紘明; 岩城正宏

  日本薬学会第140年会  2020
• Diclofenac-induced cytotoxicity in hepatocytes co-cultured with macrophages

  Kawase A; Yamashita R; Takashima O; Kaneto A; Shimada H; Iwaki M

  79th FIP World Congress of Pharmacy and Pharmaceutical Sciences  2019
• The regulatory mechanism of hepatic PGE2 disposition in carbamazepine-induced liver injury

  Iwaki M; Shimada H; Hashimoto R; Oba K; Kawase A

  IUTOX 15th International Congress of Toxicology  2019
• The role of OATP2A1 in hepatoprotection against CCl4-induced liver injury

  Shimada H; Hashimoto R; Aoki A; Yamada S; Kawase A; Iwaki M

  IUTOX 15th International Congress of Toxicology  2019
• アジュバント関節炎ラットにおける塩基性薬物の脳移行性について

  風岡顯良; 川瀬篤史; 島田紘明; 岩城正宏

  日本薬剤学会第34年会  2019
• カンカニクジュヨウ中主成分エキナコシド，アクテオシドのSGLT1阻害活性およびSGLT1介在性輸送

  羽渕風雅; 島田紘明; 岡本雄平; 川瀬篤史; 李 征; 村岡 修; 岩城正宏

  日本薬剤学会第34年会  2019
• 非ステロイド性抗炎症薬のアシルグルクロン酸抱合体生成に対するCa2+およびMg2+の促進作用

  島田紘明; 清水佑里子; 濵口健斗; 藤本和佳; 川瀬篤史; 岩城正宏

  日本薬剤学会第34回年会  2019
• 非ステロイド性抗炎症薬のアシルグルクロン酸抱合体生成・分解パラメータによる毒性予測の可能性

  熊澤佳亮; 島田紘明; 野見真人; 塩尻眞弓; 川瀬篤史; 岩城正宏

  日本薬剤学会第34回年会  2019
• ジクロフェナクのグルクロン酸抱合に与えるCaおよびMgの影響

  清水佑里子; 島田紘明; 濵口健斗; 川瀬篤史; 岩城正宏

  未来創薬医療イノベーションシンポジウム  2019
• 抗がん薬デリバリー効率の改善を目指して ～トランスポーター裏打ちタンパク質の調節を利用したトランスポーター発現低下への試み～

  廣底美保; 川瀬篤史; 井上裕太; 杉原由華; 小山勇之介; 島田紘明; 岩城正宏

  未来創薬医療イノベーションシンポジウム  2019
• 肝臓でのシトクロムP450誘導過程におけるプロテインキナーゼNの関与

  立石駿介; 川瀬篤史; 向井秀幸; 黒田真太郎; 佐藤亮介; 島田紘明; 岩城正宏; 杉浦麗子

  未来創薬医療イノベーションシンポジウム  2019
• カルバマゼピン誘発性肝障害におけるProstaglandinE2動態調節

  大場憲一; 島田紘明; 橋本凌汰; 川瀬篤史; 岩城正宏

  未来創薬医療イノベーションシンポジウム  2019
• カルバマゼピン誘発性肝障害における肝プロスタグランジンE2動態調節機構

  大場憲一; 島田紘明; 橋本凌汰; 川瀬篤史; 岩城正宏

  日本薬学会第139年会  2019
• トランスポーター裏打ちタンパク質を利用した抗がん薬デリバリー効率の改善

  川瀬篤史; 井上裕太; 廣底美保; 杉原由華; 島田紘明; 岩城正宏

  日本薬学会第139年会  2019
• 四塩化炭素誘発性肝障害におけるOATP2A1の役割

  島田紘明; 橋本凌汰; 青木 彩; 川瀬篤史; 岩城正宏

  日本薬学会第139年会  2019
• Modulation of transporter activities in hepatocytes and cancer cells by knockdown of transporter-associated proteins  [Not invited]

  Atsushi Kawase

  The 2nd Workshop for Korea-Japan Young Scientists on Pharmaceutics  2018/07
• Alteration of hepatic prostaglandin E2-related gene expression under liver injury condition

  Hiroaki Shimada; Ryota Hashimoto; Sachika Yoshikawa; Masaya Nakahama; Atsushi Kawase; Masahiro Iwaki

  59th International Conference on the Bioscience of Lipids  2018
• 非ステロイド性抗炎症薬のアシルグルクロン酸抱合体生成に対するCaおよびMgの影響

  島田紘明; 濵口健斗; 清水佑里子; 藤本和佳; 川瀬篤史; 岩城正宏

  第68回日本薬学会近畿支部総会・大会  2018
• Modulation of transporter activities in cancer cells by transporter-associated proteins

  Atsushi Kawase; Yuta Inoue; Miho Hirosoko; Hiroaki Shimada; Masahiro Iwaki

  2018 MDO/JSSX  2018
• Impact of Ca2+ and Mg2+ depletion on glucuronidation of diclofenac

  Hiroaki Shimada; Kento Hamaguchi; Yuriko Shimizu; Atsushi Kawase; Masahiro Iwaki

  2018 MDO/JSSX  2018
• Brain distribution of diphenhydramine via transporters decrease in adjuvant-induced arthritic rats

  Akira Kazaoka; Atsushi Kawase; Hiroaki Shimada; Masahiro Iwaki

  2018 MDO/JSSX  2018
• カンカニクジュヨウ中主成分エキナコシド，アクテオシドのグルコース/Na+共輸送トランスポーター阻害作用  [Not invited]

  島田紘明; 卜部裕一; 岡本雄平; 川瀬篤史; 李 征; 森川敏生; 村岡 修; 岩城正宏

  日本生薬学会第64回年会  2017
• 病態時のトランスポーター変動と特異体質性肝障害発症機序の解明  [Not invited]

  川瀬篤史

  病態情報薬学分野設立20周年記念講演会  2017
• マウス肝細胞-腹腔マクロファージ共培養系におけるグルタチオン枯渇のジクロフェナク毒性に対する影響  [Not invited]

  川瀬篤史; 金藤彩加; 石橋真央; 小林諒裕; 中村 暉; 島田紘明; 岩城正宏

  第44回日本毒性学会学術年会  2017
• 薬物誘発性肝障害に伴う肝プロスタグランジンE2動態変動  [Not invited]

  橋本凌汰; 島田紘明; 東田千代; 青木 彩; 川瀬篤史; 岩城正宏

  第59回日本脂質生化学会  2017
• Correlation between Formation of Glucuronide Metabolite and Covalent Protein Adducts of Nonsteroidal Anti-inflammatory Drugs  [Not invited]

  Hiroaki Shimada; Atsushi Kawase; Taro Ogiso; Masahiro Iwaki

  Pharmaceutical Sciences World Congress 2017  2017
• Effects of Glutathione Depletion on Diclofenac-induced Cytotoxicity in Mouse Hepatocytes  [Not invited]

  Atsushi Kawase; Ayaka Kaneto; Mao Ishibashi; Hiroaki Shimada; Masahiro Iwaki

  Pharmaceutical Sciences World Congress 2017  2017
• Effect of Hepatic and Renal Functions of Pharmacokinetics of Naproxen in Guinea Pigs: Acyl Glucuronide Concentration and Irreversible Binding to Plasma Protein  [Not invited]

  Masahiro Iwaki; Taro Ogiso; Hiroaki Shimada; Atsushi Kawase

  Pharmaceutical Sciences World Congress 2017  2017
• 能動的学習を促す双方向授業方法の検討と学習効果 -総合演習科目へのレスポンスアナライザーの導入-  [Not invited]

  大内秀一; 松野純男; 伊藤栄次; 川?直人; 川瀬篤史; 岩城正宏

  第1回日本薬学教育学会大会  2016
• Protein Kinase N Family-dependent Regulation of Hepatic Cytochrome P450 2C in Mice  [Not invited]

  Atsushi Kawase; Nobuyuki Nimura; Marina Yamashita; Yuki Ono; Koji Kubouchi; Nanae Sawada; Hiroaki Shimada; Ryosuke Satoh; Ayako Kita; Hideyuki Mukai; Masahiro Iwaki; Reiko Sugiura

  日本薬物動態学会第31回年会  2016
• Stability of Echinacoside and Acteoside, Components of Cistance Tubulosa, in Gastrointestinal Tract and Liver  [Not invited]

  Hiroaki Shimada; Yuichi Urabe; Yuhei Okamoto; Mayumi Komura; Yuki Yamashita; Atsushi Kawase; Toshio Morikawa; Osamu Muraoka; Masahiro Iwaki

  日本薬物動態学会第31回年会  2016
• Effect of ERM Protein Function Depression on ABC Transporter Activities  [Not invited]

  Yuta Inoue; Atsushi Kawase; Sayaka Nakazaki; Erika Koizumi; Hiroaki Shimada; Masahiro Iwaki

  日本薬物動態学会第31回年会  2016
• Involvement of Reactive Metabolites of Diclofenac in Cytotoxicity in Sandwich Cultured Rat Hepatocytes  [Not invited]

  Ryota Hashimoto; Atsushi Kawase; Mai Shibata; Hiroaki Shimada; Masahiro Iwaki

  日本薬物動態学会第31回年会  2016
• 多糖類を主成分とするとろみ調整剤からのグルコース生成に関する基礎的研究  [Not invited]

  松浦正佳; 岸本理咲; 加治工衛; 前田智昭; 大鳥 徹; 川瀬篤史; 島田紘明; 岩城正宏

  第10回日本薬局学会学術総会  2016
• Protein Kinase N (PKN) Family-dependent Regulation of Hepatic Cytochrome P450 2C and Metabolic Profile Analysis in PKN Mutant Mice through Targeted Metabolomics by LC-MS/MS  [Not invited]

  Atsushi Kawase; Nobuyuki Nimura; Marina Yamashita; Yuki Ono; Koji Kubouchi; Nanae Sawada; Hiroaki Shimada; Ryosuke Satoh; Ayako Kita; Hideyuki Mukai; Masahiro Iwaki; Reiko Sugiura

  第12回プロテインホスファターゼ国際カンファレンス  2016
• Influence of Radicin Knockdown on Drug Efflux Transporters of Cancer Cells  [Not invited]

  Yuta Inoue; Atsushi Kawase; Sayaka Nakazaki; Erika Koizumi; Hiroaki Shimada; Masahiro Iwaki

  第12回プロテインホスファターゼ国際カンファレンス  2016
• Contribution of Human Hepatic Cytochrome P450 Isoforms to the Stereoselective Oxidation of Carvedilol  [Not invited]

  Masahiro Iwaki; Saya Bandoh; Atsushi Kawase; Hiroshi Komura; Toshiro Niwa

  日本薬物動態学会第30回年会  2015
• Inhibitory Effects of Pravastatin on the Expression of Intestinal Niemann-pick C1 Like 1  [Not invited]

  Atsushi Kawase; Seiji Hata; Mai Takagi; Masahiro Iwaki

  日本薬物動態学会第30回年会  2015
• Protein Kinase Nファミリー遺伝子改変マウスを用いた薬物代謝酵素の解析  [Not invited]

  小野祐輝; 窪内康二; 木戸友絵; 澤田奈々; 二村信之; 山下真理奈; 川瀬篤史; 岩城正宏; 向井秀幸; 喜多綾子; 佐藤亮介; 杉浦麗子

  第65回日本薬学会近畿支部総会・大会  2015
• 炎症時におけるトランスポーター変動とERMタンパク質の関連  [Not invited]

  川瀬篤史

  第64回日本薬学会近畿支部総会・大会  2014
• Alterations in Expression and Function of ABC Transporters and ERM Proteins in Inflammation  [Not invited]

  Atsushi Kawase

  Global Education Seminar West 2014  2014
• Alterations in Expression and Function of ABC Transporters and ERM Proteins in Adjuvant-induced Arthritis Rats  [Not invited]

  Atsushi Kawase; Masahiro Iwaki

  Anti-Aging International Mini-Symposium 2014  2014
• Development for Hemiacetal Ester of New Quinolone Avoiding Chelation with Metal Containing Drugs, Together with Avoiding Pseudomembranous Colitis  [Not invited]

  Kenji Matsuyama; Tohru Ohtori; Atsushi Kawase; Masahiro Iwaki; Tetsutaro Kimachi; Yoshikazu Ishii

  19th North American Regional ISSX Meeting and 29th JSSX Meeting  2014
• Alterations in Expression and Function of Ezrin/radixin/moesin Proteins for Transporters in Adjuvant-induced Arthritis Rats  [Not invited]

  Masahiro Iwaki; Atsushi Kawase; Misato Sakata; Misaki Nakasaka; Yukio Kato

  19th North American Regional ISSX Meeting and 29th JSSX Meeting  2014
• アジュバント関節炎ラットにおけるABCトランスポーター発現変動  [Not invited]

  足立満実子; 川瀬篤史; 岩城正宏

  日本薬学会第133年会  2013
• 炎症時におけるERMタンパク質発現変動  [Not invited]

  矢田凪沙; 阪田美里; 足立満実子; 川瀬篤史; 加藤将夫; 岩城正宏

  第8回トランスポーター研究会年会  2013
• Concentration-independent Contribution of Human Hepatic Cytochrome P450 Isoforms to the Stereoselective Metabolism of Carvedilol  [Not invited]

  Masahiro Iwaki; Saya Bandoh; Megumi Itoh; Yukiko Nakamura; Hitomi Hirose; Toshiro Niwa; Hiroshi Komura; Tadatoshi Tanino; Atsushi Kawase

  日本薬物動態学会第28回年会  2013
• Alterations in Hepatic ABC Transporters and ERM Proteins in Adjuvant-induced Arthritis  [Not invited]

  Nagisa Yada; Misato Sakata; Atsushi Kawase; Yukio Kato; Masahiro Iwaki

  American Association of Pharmaceutical Scientists 2013  2013
• Effects of Adjuvant-induced Inflammation on Disposition of Diclofenac and Diclofenac Metabolites in Perfused Rat Liver  [Not invited]

  Misato Uraki; Hiroyuki Sayama; Atsushi Kawase; Yuka Matsushima; Hiroshi Komura; Masahiro Iwaki

  American Association of Pharmaceutical Scientists 2013  2013
• Effects of Pravastatin and Ezetimibe on the Expression of Intestinal Niemann-pick C1 Like 1 and ABCG5/G8  [Not invited]

  Atsushi Kawase; Seiji Hata; Mai Takagi; Masahiro Iwaki

  American Association of Pharmaceutical Scientists 2013  2013
• 高コレステロール時におけるNPC1L1発現とラット・マウス間種差  [Not invited]

  川瀬篤史; 荒木康羽; 植田元子; 瀬谷佳子; 秦 誠治; 中崎紗也香; 岩城正宏

  日本薬学会第132年会  2012
• 脂質異常症または絶食時におけるトランスポーター変動とプラバスタチン肝内動態に関する検討  [Not invited]

  川瀬篤史; 半田亜由美; 篠原広樹; 岩城正宏

  第7回トランスポーター研究会  2012
• 紅参含有ジンセノサイドのコレステロール代謝酵素CYP7Aに対する発現促進作用  [Not invited]

  川瀬篤史; 村田和也; 寒川慶一; 松田秀秋; 岩城正宏

  日本薬学会近畿支部第62回総会・大会  2012
• Stereoselective Contribution of Human Hepatic Cytochrome P450 Isoforms to the Metabolism of Carvedilol  [Not invited]

  Hitomi Hirose; Megumi Itoh; Hiroshi Komura; Tadatoshi Tanino; Atsushi Kawase; Masahiro Iwaki

  日本薬物動態学会第27回年会  2012
• エノキサシンキレート子のピボキシルエステル化による金属含有制酸剤併用時の血中エノキサシン濃度への影響  [Not invited]

  沖吉慶子; 今仲 洸; 大鳥 徹; 藤本脩太; 岡本佳世; 瀬川雅彦; 西脇敬二; 川瀬篤史; 岩城正宏; 松山賢治

  日本薬学会第131年会  2011
• 高脂肪食摂取および絶食ラットにおけるプラバスタチンの肝内動態への影響  [Not invited]

  半田亜由美; 川瀬篤史; 岩城正宏

  日本薬剤学会第26年会  2011
• メトトレキサートと非ステロイド系抗炎症薬の相互作用：非ステロイド系抗炎症薬のグルクロン酸抱合体のMRP2および4に対する輸送阻害作用  [Not invited]

  岩城正宏; 山本泰希; 半田亜由美; 川瀬篤史

  医療薬学フォーラム2011  2011
• Stereoselective Inhibitory Effects of Glucuronides of Nonsteroidal Anti-inflammatory Drugs on the Transport Mediated by Multiple Resistance-associated Protein (MRP) 2 and MRP4  [Not invited]

  Masahiro Iwaki; Taiki Yamamoto; Ayumi Handa; Atsushi Kawase

  BioMedical Transporters 2011  2011
• Alterations in P-glycoprotein in Intestine, Liver, Brain, and Kidney of the Adjuvant Arthritis Rat  [Not invited]

  Atsushi Kawase; Sari Norikane; Masahiro Iwaki

  BioMedical Transporters 2011  2011
• CYP2D遺伝的欠損DAラットにおけるカルベジロールのin vitroおよびin vivo立体選択的代謝  [Not invited]

  田中裕之; 寺口和宏; 廣瀬仁美; 大城 巧; 川瀬篤史; 岩城正宏

  第61回日本薬学会近畿大部総会・大会  2011
• 学生のニーズ把握と具体的な問題解決手法の修得を目的とした学生ワークショップの試み  [Not invited]

  安原智久; 川?直人; 八木秀樹; 川瀬篤史; 伊藤栄次; 大鳥 徹; 和田哲幸; 松山賢治; 岩城正宏

  日本薬学会第130年会  2010
• 紅蔘エキスの脂質代謝に関わるチトクロムP450およびトランスポーターに対する影響  [Not invited]

  川瀬篤史; 蒲生悠子; 田原知佳; 山田彩乃; 山下友希; 寒川慶一; 竹下文章; 村田和也; 松田秀秋; 岩城正宏

  日本薬剤学会第25年会  2010
• アジュバント関節炎発症ラットにおけるトランスポーターの変動  [Not invited]

  赤井亮介; 川瀬篤史; 法兼沙理; 岡本怜也; 岩城正宏

  日本薬剤学会第25年会  2010
• ラット肝臓および小腸におけるチトクロムP450とP-糖タンパク質の誘導に対するフェニトイン投与期間の影響  [Not invited]

  田中裕之; 川瀬篤史; 廣瀬仁美; 山崎和哉; 大鳥 徹; 岩城正宏

  日本薬剤学会第25年会  2010
• 薬学部4年制課程から6年制課程への移行に伴う本学学生の就職意識動向調査  [Not invited]

  川瀬篤史; 長井紀章; 木下充弘; 関口富美子; 桑島 博; 鈴木茂生; 西田升三; 松尾圭造; 掛樋一晃

  医療薬学フォーラム2010  2010
• 調剤薬局における薬剤師需要の動向予測に関する研究  [Not invited]

  長井紀章; 川瀬篤史; 木下充弘; 関口富美子; 桑島 博; 鈴木茂生; 西田升三; 松尾圭造; 掛樋一晃

  医療薬学フォーラム2010  2010
• 高用量レボフロキサシンの薬物動態を検討した血液透析症例  [Not invited]

  浦田元樹; 太田美由希; 北村芳子; 稲荷場ひろみ; 岡村幹夫; 川瀬篤史; 岩城正宏

  第55回日本透析医学会  2010
• 血液透析患者におけるレボフロキサシンの薬物動態の検討  [Not invited]

  太田美由希; 浦田元樹; 北村芳子; 崔 吉永; 岡村幹夫; 稲荷場ひろみ; 根来伸夫; 川瀬篤史; 岩城正宏

  第75回大阪透析研究会  2010
• エノキサシンキレート子のピボキシルエステル化による金属含有制酸剤併用時の血中エノキサシン濃度への影響  [Not invited]

  今仲 洸; 大鳥 徹; 沖吉慶子; 岡本佳世; 瀬川雅彦; 西脇敬二; 川瀬篤史; 岩城正宏

  第20回日本医療薬学会  2010
• 血液透析患者における高用量レボフロキサシン薬物動態の検討  [Not invited]

  太田美由希; 浦田元樹; 北村芳子; 崔 吉永; 岡村幹夫; 根来伸夫; 川瀬篤史; 岩城正宏

  第20回日本医療薬学会  2010
• The Effect of Fasting and Hyperlipidemia on the Disposition of Pravastatin in the In Situ Perfused Rat Liver Model  [Not invited]

  Masahiro Iwaki; Ayumi Handa; Atsushi Kawase

  Pharmaceutical Sciences World Congress 2010  2010
• Effects of Mrp2- and Mrp3-knockdown in Mice on Covalent Adduct Formation of Acyl Glucuronide Using shRNA-expressing Adenovirus Vector  [Not invited]

  Atsushi Kawase; Ayano Yamada; Taiki Yamamoto; Sayaka Tomatsu; Masahiro Iwaki

  Pharmaceutical Sciences World Congress 2010  2010
• アジュバント関節炎発症時における肝臓，小腸および脳のトランスポーターmRNA変動  [Not invited]

  宇野敏志; 浦木美里; 川瀬篤史; 岩城正宏

  日本薬学会第129年会  2009
• Changes in mRNA Expression of ABC and SLC Transporters in Liver and Intestines of the Adjuvant-induced Arthritis Rat  [Not invited]

  Satoshi Uno; Misato Uraki; Ayano Yamada; Atsushi Kawase; Masahiro Iwaki

  69th International Congress of FIP  2009
• Differences in Cytochrome P450 and Nuclear Receptor mRNA Levels in Liver and Small Intestines between SD and DA Rats  [Not invited]

  Atsushi Kawase; Akiyuki Fujii; Ryosuke Akai; Masahiro Iwaki

  69th International Congress of FIP  2009
• 紅蔘エキスの脂質代謝に関わるシトクロムP450およびトランスポーターに対する影響  [Not invited]

  山田彩乃; 竹下文章; 蒲生悠子; 田原知佳; 寒川慶一; 村田和也; 松田秀秋; 川瀬篤史; 岩城正宏

  第59回日本薬学会近畿支部総会・大会  2009
• ラットおよびマウスにおけるBCRPを介したニトロフラントイン体内動態に対するChrysinの影響  [Not invited]

  川瀬篤史; 岩城正宏

  第3回食品薬学シンポジウム  2009
• ラット肝臓および小腸におけるCYP3AとP糖タンパク質の誘導に対するフェニトイン投与期間の影響  [Not invited]

  大鳥 徹; 岡亜沙美; 川瀬篤史; 田充隆; 岩城正宏

  第18回日本医療薬学会年会  2008
• ラット肝還流法を用いたジクロフェナクの肝内動態と慢性炎症の影響  [Not invited]

  浦木美里; 松島由佳; 宇野敏志; 川瀬篤史; 岩城正宏

  日本薬剤学会第23年会  2008
• CYP2D遺伝的欠損ラットを用いたin vivo-in vitro間の薬物相互作用の予測  [Not invited]

  藤井晃行; 根來真貴子; 石窪未来; 小村 弘; 川瀬篤史; 岩城正宏

  日本薬剤学会第23年会  2008
• Alteration on the mRNA Expression of ABC and SLC Transporters in Liver and Intestine of Adjuvant-induced Arthritis Rat  [Not invited]

  Satoshi Uno; Atsushi Kawase; Masahiro Iwaki

  2nd Asian Pacific Regional ISSX Meeting  2008
• Differences in Cytochrome P450 and Nuclear Receptor mRNA Levels in Liver and Small Intestine between SD and DA Rats  [Not invited]

  Atsushi Kawase; Akiyuki Fujii; Masahiro Iwaki

  2nd Asian Pacific Regional ISSX Meeting  2008
• マイクロRNAによるIRESを介した多重遺伝子発現系における発現制御  [Not invited]

  杉尾久美子; 櫻井文教; 川瀬篤史; 岩城正宏; 川端健二; 水口裕之

  第8回遺伝子・デリバリー研究会  2008
• 各種未熟柑橘類エキスによるCYP阻害作用と成分含量との関連  [Not invited]

  藤田 忠; 川瀬篤史; 友廣教道; 増田めぐみ; 松田秀秋; 岩城正宏

  日本薬学会第128年会  2008
• トランスポーターを介した薬物相互作用：フラボノイドchrysinのラットおよびマウスbreast cancer resistance protein (Bcrp)に対する影響  [Not invited]

  川瀬篤史; 松本優香子; 羽田野素司; 岩城正宏

  日本薬学会第128年会  2008
• 塩酸デクスメデトミジンの肺循環に及ぼす作用  [Not invited]

  稲森雅幸; 塩川泰啓; 中村正人; 川瀬篤史; 岩城正宏; 古賀義久

  第54回麻酔学会  2007
• フラボノイドChrysinのマウスBcrp/ABCG2に対する影響  [Not invited]

  川瀬篤史; 松本優香子; 羽田野素司; 岩城正宏

  第2回トランスポーター研究会  2007
• Inflammation Impairs Intrinsic Chiral Inversion Activity of "Profen", Nonsteroidal Antiinflammatory Drug  [Not invited]

  Masahiro Iwaki; Misato Uraki; Satoshi Uno; Atsushi Kawase

  Pharmaceutical Sciences World Congress 2007  2007
• Effects of CAR on Bilirubin Metabolism in Mouse Collagen-induced Arthritis  [Not invited]

  Atsushi Kawase; You Tsunokuni; Masahiro Iwaki

  Pharmaceutical Sciences World Congress 2007  2007
• Substrate depletion assayによる慢性炎症モデルラットにおけるジクロフェナク代謝クリアランスの予測  [Not invited]

  藤井晃行; 宇野敏志; 川瀬篤史; 岩城正宏

  第127年会日本薬学会  2007
• 未熟ハッサクの抗アレルギー作用に関する研究  [Not invited]

  友廣教道; 森川 普; 伊藤仁久; 志浦健文; 増田めぐみ; 藤田 忠; 川瀬篤史; 岩城正宏; 我藤 雄; 文室政彦; 佐々木勝昭; 宇都宮直樹; 松田秀秋

  第127年会日本薬学会  2007
• 慢性関節炎発症時における核内レセプターの変動とビリルビン代謝に及ぼす影響  [Not invited]

  川瀬篤史; 津國 優; 岩城正宏

  第1回トランスポーター研究会  2006
• コラーゲン誘導関節炎マウスでのCAR変動がビリルビン代謝に及ぼす影響  [Not invited]

  川瀬篤史; 津國 優; 岩城正宏

  第21回日本薬物動態学会  2006
• 未熟な柑橘類果実の血行改善作用温州ミカン (Citrus unshiu)の血液レオロジー向上作用  [Not invited]

  得永雅士; 藤田 忠; 友廣教道; 増田めぐみ; 安松谷真; 江後絵美; 川瀬篤史; 岩城正宏; 松田秀秋; 佐々木勝昭; 文室政彦; 我藤 雄; 宇都宮直樹

  日本生薬学会第53回年会  2006
• アジュバント関節炎ラット肝細胞を用いたイブプロフェンのキラル変換に関する検討  [Not invited]

  宇野敏志; 浦木美里; 川瀬篤史; 岩城正宏

  第21回日本薬物動態学会  2006
• 青い柑橘類果実に新規機能性を求めて-青ウンシュウミカンの抗アレルギー作用  [Not invited]

  友廣教道; 志浦健文; 前園知子; 藤田 忠; 岩城正宏; 川瀬篤史; 松田秀秋

  第1回食品薬学シンポジウム  2006
• 抗アレルギー作用および美白作用  [Not invited]

  友廣教道; 藤田 忠; 伊藤仁久; 松田秀秋; 川瀬篤史; 岩城正宏; 我藤 雄; 佐々木勝昭; 宇都宮直樹; 久保道徳

  第35回生薬分析シンポジウム  2006
• 柑橘類果実の血行改善作用に関する研究  [Not invited]

  友廣教道; 藤田 忠; 伊藤仁久; 松田秀秋; 川瀬篤史; 岩城正宏; 我藤 雄; 佐々木勝昭; 宇都宮直樹; 久保道徳

  第126年会日本薬学会  2006
• 未熟な柑橘類果実の血行改善作用  [Not invited]

  友廣教道; 藤田 忠; 伊藤仁久; 松田秀秋; 川瀬篤史; 岩城正宏; 我藤 雄; 佐々木勝昭; 宇都宮直樹; 久保道徳

  第126年会日本薬学会  2006
• Alteration in Factors Affecting Drug Disposition during Development of Adjuvant-induced Arthritis in Rats  [Not invited]

  Atsushi Kawase; Satoshi Uno; Kana Yamamoto; Naomi Akitsu; Tomoaki Nagao; Masahiro Iwaki

  第20回年会 JSSX-ISSX合同学会  2005
• 柑橘類果実，特にハッサクCitrus hassakuの美白効果に関する研究  [Not invited]

  松田秀秋; 友廣教道; 藤田 忠; 川瀬篤史; 岩城正宏; 我藤 雄; 佐々木勝昭; 宇都宮直樹; 久保道徳

  天然薬物の応用と開発シンポジウム  2005
• DNAワクチン療法における抗原の細胞内動態の制御による細胞障害性T細胞活性の増強  [Not invited]

  川瀬篤史; 伊佐次圭子; 的野光洋; 西川元也; 高倉喜信

  第21回日本DDS学会  2005
• Improved Antigen Presentation Efficiency by Dendritic Cells with Plasmid DNA Encoding Structure-modified Antigens  [Not invited]

  Keiko Isaji; Makiya Nishikawa; Atsushi Kawase; Ayumi Yamaoka; Yoshinobu Takakura

  5th Globalization of Pharmaceutics Education Network (GPEN) International Graduates Student Meeting  2004
• In Vivo Manipulation of Dendritic Cell Migration and Activation to Elicit Immune Response by Polyplex-based DNA Vaccination  [Not invited]

  Atsushi Kawase; Ayumi Yamaoka; Makiya Nishikawa; Yoshinobu Takakura

  5th Globalization of Pharmaceutics Education Network (GPEN) International Graduates Student Meeting  2004
• Control of Intracellular Trafficking of Genetically Delivered Antigens in Dendritic Cells for Improved DNA Vaccination  [Not invited]

  Keiko Isaji; Makiya Nishikawa; Atsushi Kawase; Ayumi Yamaoka; Yoshinobu Takakura

  Pharmaceutical Sciences World Congress 2004  2004
• Increased Dendritic Cell Migration to the Vaccination Site and Enhanced Immune Response by Polyplex-based DNA Vaccine  [Not invited]

  Atsushi Kawase; Ayumi Yamaoka; Makiya Nishikawa; Yoshinobu Takakura

  Pharmaceutical Sciences World Congress 2004  2004
• メチル化BSAを利用したプラスミドDNAによる抗原特異的抗体産生の増大  [Not invited]

  伊佐次圭子; 川瀬篤史; 山岡あゆみ; 西川元也; 高倉喜信

  第13回アンチセンスシンポジウム  2003
• カチオン性高分子/プラスミドDNA複合体化によるDNAワクチン効果の増強およびそのメカニズム  [Not invited]

  川瀬篤史; 伊佐次圭子; 小林直樹; 西川元也; 高倉喜信

  日本DDS学会第19年会  2003
• ハイドロダイナミクス (Hydrodynamics)法による肝細胞への効率的遺伝子デリバリーメカニズム  [Not invited]

  小林直樹; 川瀬篤史; 西川元也; 高倉喜信

  日本DDS学会第19年会  2003
• カチオン性高分子キャリアーを用いたプラスミドDNA複合体化によるDNAワクチン効果の制御  [Not invited]

  川瀬篤史; 伊佐次圭子; 小林直樹; 西川元也; 高倉喜信

  日本薬剤学会第18年会  2003
• Control of Disposition Characteristics of Plasmid DNA after Local Administration by Complexation with Cationic Macromolecules  [Not invited]

  Atsushi Kawase; Naoki Kobayashi; Kiyoshi Yamaoka; Yoshinobu Takakura

  29th Annual Meeting and Exposition of the Controlled Release Society  2002
• メチル化BSA複合体化によるプラスミドDNAの局所投与時の動態および免疫応答の制御  [Not invited]

  川瀬篤史; 小林直樹; 高倉喜信

  遺伝子・デリバリー研究会第2回シンポジウム  2002
• メチル化BSA/プラスミドDNA複合体の筋肉内投与の体内動態と遺伝子発現  [Not invited]

  川瀬篤史; 山岡 清; 高倉喜信

  日本薬学会第122年会  2002
• プラスミドDNAの局所投与時の体内動態と遺伝子発現機構に関する検討  [Not invited]

  川瀬篤史; 山岡 清; 高倉喜信

  日本薬剤学会第16年会  2001

MISC

• 芳香族L-アミノ酸脱炭酸酵素を阻害しないD-carbidopaはH₂S産生酵素cystathionine-β-synthaseを阻害することでTNBS誘起結腸痛を抑制する

  井場祐里子; 本夛泉侑; 坪田真帆; 川瀬篤史; 岡田卓哉; 豊岡尚樹; 川畑篤史  日本薬理学雑誌  157-  (Supplement)  2022
• 砂漠人参カンカニクジュヨウの血糖上昇抑制作用メカニズムの解明

  島田紘明; 卜部裕一; 岡本雄平; 李征; 川瀬篤史; 森川敏生; 森川敏生; 村岡修; 村岡修; 村岡修; 岩城正宏; 岩城正宏; 岩城正宏  生体膜と薬物の相互作用シンポジウム講演要旨集  39th-  56‐57  2017/10
• カンカニクジュヨウ中主成分エキナコシド,アクテオシドのグルコース/Na⁺共輸送トランスポーター阻害作用

  島田紘明; 卜部裕一; 岡本雄平; 川瀬篤史; 李征; 森川敏生; 森川敏生; 村岡修; 村岡修; 村岡修; 岩城正宏; 岩城正宏; 岩城正宏  日本生薬学会年会講演要旨集  64回-  113  -113  2017/08
• Diclofenac-induced toxicity in glutathione-depleted isolated murine hepatocytes co-cultured with peritoneal macrophages

  KAWASE Atsushi; KANETO Ayaka; ISHIBASHI Mao; KOBAYASHI Akihiro; NAKAMURA Hikaru; SHIMADA Hiroaki; IWAKI Masahiro  Annual Meeting of the Japanese Society of Toxicology  44.1-  O-16  2017
• A trial of the integrated cross-field pharmaceutical education in the first year of Faculty of Pharmacy

  Tomohisa Yasuhara; Naohito Kawasaki; Hideki Yagi; Eiji Itoh; Atsushi Kawase; Toru Otori; Tetsuyuki Wada; Kenji Matsuyama; Masahiro Iwaki  Yakugaku Zasshi  130-  (12)  1647  -1653  2010/12
• P1-245 エノキサシンキレート子のピボキシルエステル化による金属含有制酸剤併用時の血中エノキサシン濃度への影響(一般演題 ポスター発表,薬物動態・TDM・投与設計,臨床から学び臨床へと還元する医療薬学)

  今仲 洸; 大鳥 徹; 沖吉 慶子; 岡本 佳世; 瀬川 雅彦; 西脇 敬二; 川瀬 篤史; 岩城 正宏; 松山 賢治  日本医療薬学会年会講演要旨集  20-  328  -328  2010/10
• P2-258 血液透析患者における高用量レボフロキサシン薬物動態の検討(一般演題 ポスター発表,薬物動態・TDM・投与設計,臨床から学び臨床へと還元する医療薬学)

  太田 美由希; 浦田 元樹; 北村 芳子; 崔 吉永; 岡村 幹夫; 稲荷場 ひろみ; 根来 伸夫; 川瀬 篤史; 岩城 正宏  日本医療薬学会年会講演要旨集  20-  432  -432  2010/10
• 20-P3-469 ラット肝臓および小腸におけるCYP3AとP糖タンパク質の誘導に対するフェニトイン投与期間の影響(薬物動態(基礎),来るべき時代への道を拓く)

  大鳥 徹; 岡 亜沙美; 川瀬 篤史; 高田 充隆; 岩城 正宏  日本医療薬学会年会講演要旨集  18-  357  -357  2008/09
• Gastrointestinal Absorption of Hesperidin and Hesperetin after Oral Administration of Immature Citrus Unshiu Extract to Rats

  Fujita Tadashi; Kawase Atsushi; Nishijima Nanae; Masuda Megumi; Matsuda Hideaki; Iwaki Masahiro  The Japanese journal of pharmacognosy  62-  (1)  8  -14  2008/02
• DIFFERENCES IN CYTOCHROME P450 AND NUCLEAR RECEPTOR MRNA LEVELS IN LIVER AND SMALL INTESTINE BETWEEN SD AND DA RATS

  Atsushi Kawase; Akiyuki Fujii; Masahiro Iwaki  DRUG METABOLISM REVIEWS  40-  68  -69  2008
• 塩酸デクスメデトミジンの体循環および肺循環に及ぼす影響

  稲森 雅幸; 川瀬 篤史; 岩城 正宏; 古賀 義久  近畿大学医学雑誌  32-  (4)  243  -251  2007/12
• Manipulation of immune responses by DNA vaccination through controlled local pharmacokinetics of DNA by complex formation with cationic macromolecule

  A Kawase; K Isaji; N Kobayashi; M Nishikawa; Y Takakura  MOLECULAR THERAPY  7-  (5)  S267  -S267  2003/05

Awards & Honors

• 2016/10 日本薬局学会 日本薬局学会ポスター優秀演題賞
   

  受賞者: 川瀬篤史
• 2014/12 日本薬剤学会 Global Education Seminar Presentation Award
   

  受賞者: 川瀬篤史
• 2014/01 日本薬学会 日本薬学会近畿支部奨励賞
   

  受賞者: 川瀬篤史
• 2002/05 遺伝子・デリバリー研究会 遺伝子・デリバリー研究会奨励賞
  

Research Grants & Projects

• トランスポーター周辺タンパク質標的型ペプチドを用いた抗がん薬デリバリー効率の改善

  独立行政法人 日本学術振興会 科学研究費助成（基盤研究(C))：

  Date (from‐to) : 2021/04 -2024/03 

  Author : 川瀬篤史
• トランスポーター周辺タンパク質は抗がん薬多剤耐性克服のターゲットとなり得るか？

  独立行政法人 日本学術振興会 科学研究費助成（基盤研究(C))：

  Date (from‐to) : 2018/04 -2021/03 

  Author : 川瀬 篤史
• 特異体質性肝障害にアシルCoAチオエステル中間代謝物は関与しているか？

  独立行政法人 日本学術振興会：科学研究費助成（基盤研究(C))

  Date (from‐to) : 2017/04 -2020/03 

  Author : 岩城正宏
• 標的プロテオミクス法による炎症時のトランスポーター機能および薬物動態解析

  近畿大学 学内研究助成金（奨励）

  Date (from‐to) : 2017/04 -2018/03
• ERMタンパク質リン酸化状態およびトランスポーター機能に対する炎症因子の影響

  独立行政法人 日本学術振興会：科学研究費助成（若手研究 (B)）

  Date (from‐to) : 2016/04 -2018/03 

  Author : 川瀬篤史
• 炎症時におけるERMタンパク質変動とトランスポーター機能との関連

  独立行政法人 日本学術振興会：科学研究費助成（若手研究 (B)）

  Date (from‐to) : 2014/04 -2016/03 

  Author : 川瀬篤史
• 種々の炎症モデルにおけるERMタンパク質およびトランスポーター機能に対する影響

  近畿大学 学内研究助成金（奨励）

  Date (from‐to) : 2014/04 -2015/03
• アデノウイルスベクターを利用した特異体質性肝障害機序の解明

  公益財団法人 上原記念生命科学財団：研究奨励金

  Date (from‐to) : 2012/04 -2013/03 

  Author : 川瀬篤史
• 反応性代謝物を介する肝障害発現に関与する機能タンパク質の解明

  独立行政法人 日本学術振興会：科学研究費助成（基盤研究(C))

  Date (from‐to) : 2011/04 -2013/03 

  Author : 岩城正宏
• アデノウイルスベクターを利用したNSAIDsの肝毒性発現機構の解明

  近畿大学 学内研究助成金（奨励）

  Date (from‐to) : 2010/04 -2011/03
• Development of an adenovirus vector containing microRNA-regulated gene expression system

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (A)

  Date (from‐to) : 2008 -2010 

  Author : SAKURAI Fuminori; MIZUGUCHI Hiroyuki; KAWABATA Kenji; KATAYAMA Kazufumi; TASHIRO Katsuhisa; KONDOH Masuo; YAGI Kiyohito; NAKAMURA Shin-ichiro; KAWASE Atsushi; IWAKI Masahiro; HAYAKAWA Takao; FUJIWARA Toshiyoshi; SUZUKI Takayuki; SUGIO Kumiko; SHIMIZU Kahori; BENNETT David Mark Gilfedder; TOMITA Kyoko

   

  In this study, we developed the adenovirus (Ad) vectors which exhibited enhanced safety profiles by incorporating microRNA (miRNA)-regulated gene expression system. For example, (1)an Ad vector which shows reduction in the transgene expression in the liver and spleen by insertion of sequences complementary to liver- and spleen-specific miRNA, respectively, (2) an Ad vector which exhibits reduction in the leaky expression of Ad genes by insertion of miRNA complementary sequences into 3'-untranslated region of E2A or E4 genes, (3) a oncolytic Ad which shows reduced replication in normal cells by insertion of sequences complementary to normal cell-specific miRNAs, were developed.
• フラボノイドまたはフラノクマリンによるBCRP阻害効果と臓器選択的薬物送達への応用

  近畿大学 学内研究助成金（奨励）

  Date (from‐to) : 2007/04 -2008/03

Others

• 2017/04 -2017/04  標的プロテオミクス法による炎症時のトランスポーター機能および薬物動態解析 

  近畿大学学内奨励研究助成金 SR03
• 2015/04 -2015/04  アクティブ・ラーニングを取り入れた双方向授業の導入と評価法の構築―学生参加型学習推進のための問題抽出とその対策 

  近畿大学学内研究助成金 21世紀教育開発奨励金【教育推進研究助成金】KS01
• 2014/04 -2014/04  種々の炎症モデルにおけるERMタンパク質およびトランスポーター機能に対する影響 

  近畿大学学内奨励研究助成金 SR04
• 2010/04 -2010/04  アデノウイルスベクターを利用したNSAIDSの肝毒性機構の解明 

  近畿大学学内奨励研究助成金 SR03
• 2007/04 -2007/04  フラボノイドまたはフラノクマリンによるBCRP阻害効果と臓器選択的薬物送達への応用 

  近畿大学学内奨励研究助成金 GS05

Other link

researchmap

https://researchmap.jp/akawase