Analysis of inhibition kinetics of three beverage ingredients, bergamottin, dihydroxybergamottin and resveratrol, on CYP2C9 activity

被引：4
作者：
Akiyoshi, Takeshi [1 ]
Uchiyama, Marika [1 ]
Inada, Rino [1 ]
Imaoka, Ayuko [1 ]
Ohtani, Hisakazu [1 ,2 ,3 ]
机构：
[1] Keio Univ, Fac Pharm, Div Clin Pharmacokinet, Minato Ku, 1-5-30 Shibakoen, Tokyo 1058512, Japan
[2] Keio Univ, Sch Med, Dept Clin Pharm, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan
[3] Keio Univ Hosp, Dept Pharm, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan
来源：
DRUG METABOLISM AND PHARMACOKINETICS | 2022年 / 42卷
关键词：
Time-dependent inhibition; Mechanism-based inhibition; Grapefruit juice; Noncompetitive-inhibition; Fruit components; Warfarin; GRAPEFRUIT JUICE COMPONENTS; CYTOCHROME-P450; PHARMACOKINETICS; PREDICTION; SIMULATION; MODELS; TIME;
D O I：
10.1016/j.dmpk.2021.100429
中图分类号：
R9 [药学];
学科分类号：
1007 ;
摘要：
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 (k(inact,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 (K-i) of 3.64 mu M. 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) (C) 2021 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
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页数：6
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