KINDAI UNIVERSITY


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KAWASE Atsushi

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FacultyDepartment of Pharmacy
PositionAssociate Professor
Degree
Commentator Guidehttps://www.kindai.ac.jp/meikan/689-kawase-atsushi.html
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Last Updated :2020/09/30

Education and Career

Academic & Professional Experience

  •   2018 04 ,  - 現在, Associate professor, Kindai University
  •   2008 04 ,  - 2018 03 , Faculty of Pharmacy, Kindai University
  •   2007 04 ,  - 2008 03 , Faculty of Pharmacy, Kindai University
  •   2005 04 ,  - 2007 03 , Faculty of Pharmacy, Kindai University

Research Activities

Research Areas

  • Life sciences, Clinical pharmacy

Research Interests

  • drug delivery, inflammation, toxicity, transporter

Published Papers

  • 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, European journal of clinical pharmacology, 76(1), 117 - 125, Jan. 2020 , Refereed
    Summary: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.
  • 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, Inflammation, Oct. 2019 , 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, Journal of Pharmacy & Pharmaceutical Sciences, 2019 , Refereed
  • Impact of the CYP3A5*1 Allele on the Pharmacokinetics of Tacrolimus in Japanese Heart Transplant Patients., Uno T, Wada K, Matsuda S, Terada Y, Oita A, Kawase A, Takada M, European journal of drug metabolism and pharmacokinetics, European journal of drug metabolism and pharmacokinetics, 43(6), 665 - 673, Apr. 2018 , Refereed
  • 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, DRUG METABOLISM REVIEWS, 47, 275, Nov. 20 2015 , Refereed
  • 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, 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, Pharmacology & Pharmacy, 4, 240 - 243, 2013
  • 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, DRUG METABOLISM REVIEWS, 40, 213 - 214, 2008 , Refereed
  • 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, Shoyakugaku zasshi, 62, 8 - 14, 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, Med J Kinki Univ, Med J Kinki Univ, 32, 243 - 251, 2007
  • 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, Prostaglandins, leukotrienes, and essential fatty acids, 155, 102081 - 102081, Feb. 21 2020 , Refereed
    Summary: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.
  • 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, NATURAL PRODUCT COMMUNICATIONS, 14(10), Oct. 2019 , Refereed
    Summary: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, British journal of clinical pharmacology, 85(9), 2176 - 2178, Sep. 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, 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
    Summary: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.
  • 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, European journal of clinical pharmacology, 75(1), 67 - 75, Jan. 2019 , Refereed
    Summary: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.
  • 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, European Journal of Pharmaceutical Sciences, 112, 132 - 138, Jan. 15 2018 , Refereed
    Summary: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.
  • 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, Journal of Toxicological Sciences, 43(1), 59 - 63, 2018 , Refereed
    Summary: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.
  • 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, JOURNAL OF FUNCTIONAL FOODS, 39, 91 - 95, Dec. 2017 , Refereed
    Summary: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, EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 42(3), 519 - 526, Jun. 2017
    Summary: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, INTERNATIONAL JOURNAL OF TOXICOLOGY, 36(3), 260 - 267, May 2017
    Summary: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, JOURNAL OF PHARMACEUTICAL SCIENCES, 106(4), 1175 - 1182, Apr. 2017
    Summary: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, DRUG METABOLISM AND DISPOSITION, 45(3), 316 - 324, Mar. 2017
    Summary: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.
  • Stereoselective hepatic disposition of ibuprofen in the perfused liver of rat with adjuvant-induced arthritis, Misato Uraki, Atsushi Kawase, Masahiro Iwaki, XENOBIOTICA, XENOBIOTICA, 47(11), 943 - 950, 2017
    Summary: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, JOURNAL OF PHARMACY AND PHARMACOLOGY, 68(12), 1527 - 1534, Dec. 2016
    Summary: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, DRUG METABOLISM AND PHARMACOKINETICS, 31(6), 425 - 432, Dec. 2016
    Summary: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, ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES, 11(5), 662 - 667, Oct. 2016
    Summary: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, EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 41(4), 457 - 463, Aug. 2016
    Summary: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, EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 41(3), 301 - 307, Jun. 2016
    Summary: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, JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 356(2), 366 - 374, Feb. 2016
    Summary: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, International Journal of Pharmacy and Pharmaceutical Sciences, 8(12), 130 - 134, 2016
    Summary: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.
  • 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, EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 40(2), 239 - 244, Jun. 2015
    Summary: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, JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, 18(5), 765 - 772, 2015
    Summary: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, JOURNAL OF PHARMACEUTICAL SCIENCES, 103(12), 4058 - 4065, Dec. 2014
    Summary: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, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 134(9), 925 - 929, Sep. 2014
    Summary: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, JOURNAL OF PHARMACEUTICAL SCIENCES, 103(8), 2556 - 2564, Aug. 2014
    Summary: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, JOURNAL OF NATURAL MEDICINES, 68(2), 395 - 401, Apr. 2014
    Summary: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, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 134(2), 171 - 177, Feb. 2014
    Summary: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, Journal of Natural Medicines, 67(3), 545 - 553, Jul. 2013
    Summary: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, XENOBIOTICA, 43(3), 246 - 252, Mar. 2013
    Summary: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.
  • 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, JOURNAL OF HEALTH SCIENCE, 57(5), 414 - 419, Oct. 2011
    Summary: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, CLINICAL CANCER RESEARCH, 17(9), 2807 - 2818, May 2011
    Summary: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, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 130(12), 1647 - 1653, Dec. 2010
    Summary: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, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 74(5), 918 - 922, May 2010
    Summary: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, JOURNAL OF HEALTH SCIENCE, 55(5), 809 - 813, Oct. 2009
    Summary: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, JOURNAL OF CONTROLLED RELEASE, 135(3), 227 - 233, May 2009
    Summary: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, JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, 12(2), 150 - 163, 2009
    Summary: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, BIOPHARMACEUTICS & DRUG DISPOSITION, 30(1), 49 - 54, Jan. 2009
    Summary: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, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 31(5), 925 - 930, May 2008
    Summary: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, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 72(4), 1015 - 1022, Apr. 2008
    Summary: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, JOURNAL OF NATURAL MEDICINES, 62(2), 202 - 206, Apr. 2008
    Summary: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.
  • 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, XENOBIOTICA, 38(11), 1410 - 1421, 2008
    Summary: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, XENOBIOTICA, 38(5), 482 - 495, 2008
    Summary: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.
  • 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, DRUG METABOLISM AND PHARMACOKINETICS, 23(3), 196 - 206, 2008
    Summary: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, JOURNAL OF HEALTH SCIENCE, 53(5), 622 - 624, Oct. 2007
    Summary: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, DRUG METABOLISM AND DISPOSITION, 35(2), 256 - 261, Feb. 2007
    Summary: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.
  • 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, DRUG METABOLISM AND PHARMACOKINETICS, 22(4), 313 - 321, 2007
    Summary: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, XENOBIOTICA, 37(4), 366 - 374, 2007
    Summary: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, VACCINE, 24(27-28), 5535 - 5545, Jul. 2006
    Summary: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.
  • 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, JOURNAL OF PHARMACEUTICAL SCIENCES, 94(12), 2656 - 2666, Dec. 2005
    Summary: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, INTERNATIONAL JOURNAL OF PHARMACEUTICS, 293(1-2), 291 - 301, Apr. 2005
    Summary: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, JOURNAL OF GENE MEDICINE, 6(4), 455 - 463, Apr. 2004
    Summary: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, JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 308(2), 688 - 693, Feb. 2004
    Summary: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, JOURNAL OF PHARMACEUTICAL SCIENCES, 92(6), 1295 - 1304, Jun. 2003
    Summary: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

  • Modulation of transporter activities in hepatocytes and cancer cells by knockdown of transporter-associated proteins, Atsushi Kawase, The 2nd Workshop for Korea-Japan Young Scientists on Pharmaceutics,   2018 07 10

Misc

  • 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 26 , http://jglobal.jst.go.jp/public/201802279906981382
  • 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, 64th, 113,   2017 08 25 , http://jglobal.jst.go.jp/public/201802265898730700
  • 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 , 10.1248/yakushi.130.1647, http://ci.nii.ac.jp/naid/130000451722
    Summary: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. © 2010 The Pharmaceutical Society of Japan.
  • 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 20 , http://ci.nii.ac.jp/naid/110008729795
    Summary: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 INTESTINE BETWEEN SD AND DA RATS, Atsushi Kawase, Akiyuki Fujii, Masahiro Iwaki, DRUG METABOLISM REVIEWS, 40, 68, 69,   2008
  • 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