Variation in the inhibitory potency of terbinafine among genetic variants of CYP2D6
Variation in the inhibitory potency of terbinafine among genetic variants of CYP2D6
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DOI：
10.1016/j.dmpk.2015.04.003
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发表时间：
2015-08-01
影响因子：
2.1
通讯作者：
Ohtani, Hisakazu
中科院分区：
文献类型：
--
作者：
Akiyoshi, Takeshi;Ishiuchi, Miho;Ohtani, Hisakazu
细胞色素P450 2D 6（CYP 2D 6）是一种高度多态性的酶，参与许多药物的代谢。特比萘芬（TER）是一种CYP 2D 6抑制剂，在临床上会引起持续的药物相互作用;然而，其抑制机制及其抑制效力在CYP 2D 6遗传变异体之间的差异仍有待研究。本研究旨在探讨TER的抑制机制及其在CYP 2D 6三种变异体（CYP2D6.1、CYP2D6.2和CYP2D6.10）之间的抑制效力差异。在竞争性抑制研究中，根据在TER存在或不存在的情况下CYP 2D 6的去甲基化来评估CYP 2D 6的代谢活性，并通过将酶与TER预孵育来检查抑制作用的时间依赖性。TER对CYP2D6.2和CYP2D6.10的抑制作用弱于对CYP2D6.1的抑制作用;即，TER对CYP2D6.1、CYP2D6.2和CYP2D6.10的Ki值（导致半数最大抑制的抑制剂浓度）分别为0.0525、0.355和1.85 μ M。由于TER对CYP2D6.10的K-i值是对CYP2D6.1的K-i值的35.2倍，因此在估计涉及TER的药物相互作用的严重程度时，应考虑受试者的CYP 2D 6基因型。Copyright（C）2015，The Japanese Society for the Study of Xenobiotics.由爱思唯尔有限公司出版。保留所有权利。
Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic enzyme that is involved in the metabolism of many drugs. Terbinafine (TER) is a CYP2D6 inhibitor and causes persistent drug interactions in the clinical setting; however, its inhibitory mechanism and the differences in its inhibitory potency among genetic variants of CYP2D6 remain to be investigated. This study aimed to investigate the inhibitory mechanism of TER and the differences in its inhibitory potency among three CYP2D6 variants, CYP2D6.1, CYP2D6.2, and CYP2D6.10.In a competitive inhibition study, the metabolic activity of the CYP2D6 was assessed based on their demethylation of dextromethorphan in the presence or absence of TER, and the time-dependency of the inhibitory effects were examined by preincubating the enzymes with TER.TER had weaker inhibitory effects on CYP2D6.2 and CYP2D6.10 than on CYP2D6.1; i.e., TER exhibited K-i values (the concentration of inhibitor that results in half-maximal inhibition) of 0.0525, 0.355, and 1.85 mu M for CYP2D6.1, CYP2D6.2, and CYP2D6.10, respectively. The inhibitory effects of TER were not time-dependent.Since TER's K-i value for CYP2D6.10 was 35.2-fold higher than its K-i value for CYP2D6.1, the CYP2D6 genotype of subjects should be taken into account when estimating the severity of drug interactions involving TER. Copyright (C) 2015, The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.