Effects of acid and lactone forms of statins on S-warfarin 7-hydroxylation catalyzed by human liver microsomes and recombinant CYP2C9 variants (CYP2C9.1 and CYP2C9.3) |
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| Affiliation: | 1. Department of Pharmacy, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto, 390-8621, Japan;2. Department of Biochemical Pharmacology and Toxicology, Graduate School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto, 390-8621, Japan;1. Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Sojo University, Ikeda 4-22-1, Nishi-Ku, Kumamoto, 860-0082, Japan;2. Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan;3. Department of Chemistry, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan;4. Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;5. DDS Research Institute, Sojo University, Ikeda 4-22-1, Nishi-Ku, Kumamoto, 860-0082, Japan;1. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan;2. Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima-city, Japan;1. Novartis Institutes for Biomedical Research, Basel, Switzerland;2. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA;3. IIS-Management, Novartis Healthcare Pvt. Ltd., Hyderabad, India;1. Discovery Technology Laboratories, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan;2. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan;1. Division of Pharmaceutics, Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen Minato-ku, Tokyo, 105-8512, Japan;2. Division of Bioorganic and Medicinal Chemistry, Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen Minato-ku, Tokyo, 105-8512, Japan;1. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan;2. Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima-city, Japan |
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| Abstract: | The inhibition of CYP2C9-mediated warfarin metabolism by acid or lactone forms of statin converted in the body and effects of CYP2C9 genetic variants on their inhibition are not fully understood. Here, the effects of acid and lactone forms of statins on S-warfarin 7-hydroxylation were investigated in vitro. S-Warfarin 7-hydroxylase activities of human liver microsomes (HLMs), recombinant CYP2C9.1 (rCYP2C9.1), and rCYP2C9.3 (Ile359Leu variant) in the presence of statins were determined by high-performance liquid chromatography. Lactone forms of atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin inhibited the activity of HLMs more potently than the corresponding acid forms, whereas fluvastatin acid showed stronger inhibition than fluvastatin lactone. When the effects of statins on rCYP2C9 variants were examined, inhibition profiles of acid versus lactone forms of statins except for fluvastatin were similar between rCYP2C9.1 and rCYP2C9.3. However, the degrees of inhibition by atorvastatin lactone, fluvastatin acid, fluvastatin lactone, lovastatin lactone, and pitavastatin lactone (Ki values) were significantly different between these variants. These results indicated that lactone forms of statins other than fluvastatin showed more potent inhibition of CYP2C9-catalyzed S-warfarin 7-hydroxylation than the corresponding acid forms. Furthermore, our results indicated that Ile359Leu substitution in CYP2C9 affected the inhibitory potencies of statins. |
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| Keywords: | Statin Warfarin CYP2C9 Inhibition Polymorphism |
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