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Analysis of inhibition kinetics of three beverage ingredients,bergamottin, dihydroxybergamottin and resveratrol,on CYP2C9 activity |
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| Institution: | 1. Division of Clinical Pharmacokinetics, Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan;2. Department of Clinical Pharmacy, School of Medicine, Keio University, 35, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan;3. Department of Pharmacy, Keio University Hospital, 35, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan;1. Chemist. of Funct. Mol., Grad. Sch. Biomed. Sci., Nagasaki Univ, Japan;2. PRESTO, JST, Japan;1. Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan;2. Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan;3. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan;1. Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan;2. Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan;3. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan;1. Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, 606-8507, Japan;2. Department of Pharmacy, Kobe University Hospital, Chuo-ku, Kobe, 650-0017, Japan;3. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan;4. Department of Urology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan;5. Department of Nephrology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan;6. Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan |
| Abstract: | Some grapefruit juice (GFJ) ingredients and resveratrol, a fruit-derived phytoalexin, are known to inhibit cytochrome P450 (CYP) 2C9. However, their inhibition modes and detailed inhibition kinetics remain undetermined. This study aimed to investigate the inhibitory effects of two GFJ ingredients, bergamottin (BG) and dihydroxybergamottin (DHB), and resveratrol on CYP2C9 activity in vitro. DHB inhibited CYP2C9 activity, as assessed by warfarin 7-hydroxylation, in a preincubation time-dependent manner (i.e., mechanism-based inhibition; MBI), in the same manner as CYP2C19 and CYP3A4. The maximal inactivation rate (kinact,max) was 0.0638 min?1 and 0.12- and 0.26-fold of that for CYP2C19 and CYP3A4, respectively. BG showed both MBI and time-independent competitive inhibition. Resveratrol showed non-competitive inhibition with an inhibition constant (Ki) of 3.64 μM. Unlike the inhibition of CYP2C19 and CYP3A4, resveratrol did not induce MBI. These findings are important for estimating the risk of drug interactions between CYP2C9 substrates and some beverages. (146 words) |
| Keywords: | Time-dependent inhibition Mechanism-based inhibition Grapefruit juice Noncompetitive-inhibition Fruit components Warfarin MBI"} {"#name":"keyword" "$":{"id":"kwrd0045"} "$$":[{"#name":"text" "_":"mechanism-based inhibition GFJ"} {"#name":"keyword" "$":{"id":"kwrd0055"} "$$":[{"#name":"text" "_":"grapefruit juice RSV"} {"#name":"keyword" "$":{"id":"kwrd0065"} "$$":[{"#name":"text" "_":"resveratrol DHB"} {"#name":"keyword" "$":{"id":"kwrd0075"} "$$":[{"#name":"text" "_":"6′ 7′-dihydroxybergamottin BG"} {"#name":"keyword" "$":{"id":"kwrd0085"} "$$":[{"#name":"text" "_":"bergamottin AUC"} {"#name":"keyword" "$":{"id":"kwrd0095"} "$$":[{"#name":"text" "_":"area under the plasma concentration-time curve maximum plasma concentration the observed inactivation rate the maximal inactivation rate the concentration of the inhibitor that gives half-maximal rate of inactivation apparent metabolic velocity corrected metabolic velocity |
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