Inhibitory effects of sesamin on CYP2C9-dependent 7-hydroxylation of S-warfarin |
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| Affiliation: | 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. Division of Signal Responses, Biosignal Research Center, Kobe University, 1-1 Rokkodai Nada, Kobe, 657-8501, Japan;2. Division of Signal Responses, Biosignal Research Center, Kobe University, 1-1 Rokkodai Nada, Kobe, 657-8501 Japan;1. Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan;2. Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan;3. WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan;1. Regulation and Prequalification, Access to Medicines and Health Products, World Health Organization, Avenue Appia 20, 1211, Geneva 27, Switzerland;2. Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya, 467-8603, Japan;3. Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, 980-8578, Japan;4. Division of Risk Assessment, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki-ku, Kanagawa, 210-9501, Japan;1. Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima City, Kagoshima, 890-8580, Japan;2. Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, 642-0017, Japan;3. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan |
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| Abstract: | A recent report demonstrated that sesamin strongly and non-competitively inhibits S-warfarin 7-hydroxylation activity in human liver microsomes with a Ki value of 0.2 μM. This finding suggests that sesamin predominantly binds to CYP2C9 at another site for which it has a higher affinity than its affinity for the active site, thereby inhibiting the activity of CYP2C9 non-competitively. In this study, we found that sesamin competitively inhibited the 7-hydroxylation activity of S-warfarin in human liver microsomes with a Ki value of 15.7 μM. In addition, the recombinant CYP2C9-dependent 7-hydroxylation activity of S-warfarin was competitively inhibited by sesamin with a Ki value of 13.1 μM. These results are consistent with the fact that sesamin is a good substrate of CYP2C9, and its activity follows Michaelis-Menten kinetics. As the plasma concentration of sesamin after its administration is usually lower than 0.01 μM, the inhibition of S-warfarin metabolism by sesamin does not appear to be severe. |
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| Keywords: | Sesamin Warfarin CYP2C9 Human liver microsomes Competitive inhibition P450 or CYP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0040" }," $$" :[{" #name" :" text" ," _" :" cytochrome P450 UGT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0050" }," $$" :[{" #name" :" text" ," _" :" UDP-glucuronosyl transferase SULT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0060" }," $$" :[{" #name" :" text" ," _" :" sulfotransferase HPLC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0070" }," $$" :[{" #name" :" text" ," _" :" high performance liquid chromatography SC1" },{" #name" :" keyword" ," $" :{" id" :" kwrd0080" }," $$" :[{" #name" :" text" ," _" :" sesamin monocatechol SC2" },{" #name" :" keyword" ," $" :{" id" :" kwrd0090" }," $$" :[{" #name" :" text" ," _" :" sesamin dicatechol |
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