Inter-individual Variability of In Vivo CYP2D6 Activity in Different Genotypes
Inter-individual Variability of In Vivo CYP2D6 Activity in Different Genotypes
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DOI：
10.2133/dmpk.dmpk-11-rg-078
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发表时间：
2012-08-25
影响因子：
2.1
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
--
作者：
Chiba, Koji;Kato, Motohiro;Sugiyama, Yuichi
细胞色素P450 2D6 （CYP2D6）具有大量的遗传多态性，参与多种底物的代谢。右美沙芬（DM）是一种众所周知的CYP2D6探测药物，代谢比（MR）常被用来测量体内CYP2D6酶的活性。利用DM MR的文献值，通过蒙特卡罗模拟估计各基因型CYP2D6肝内清除率（CLint,h,2D6）的个体间变异性，发现CYP2D6*1纯合子和CYP2D6*1杂合子与零等位基因的变异系数（CV）分别为43%和56%。CYP2D6*2和CYP2D6*10纯合子的变异率分别为63%和66%，而CYP2D6*2与零等位基因和CYP2D6*10与零等位基因的杂合子的变异率分别为125%和109%。基于亚洲人和高加索人CYP2D6基因型的变异性和报告频率，广泛代谢产物CLint，h，2D6的个体间变异性估计为60 - 70%，这提供了与DM，托特罗定，利培酮和托莫西汀的文献值相当的AUC变异性。这表明，每个基因型中CLint，h，2D6的个体间变异性有助于估计区域人群中CYP2D6底物的AUC变异性。
Cytochrome P450 2D6 (CYP2D6), which has a large number of genetic polymorphisms, is involved in the metabolism of a wide range of substrates. Dextromethorphan (DM) is a well-known probe drug for CYP2D6 and metabolic ratio (MR) is often used to measure the enzyme activity in vivo. Using the literature values of DM MR, we estimated the inter-individual variability of CYP2D6 hepatic intrinsic clearance (CLint,h,2D6) in each genotype by Monte Carlo simulation and found that the homozygote of CYP2D6*1 and the heterozygote of CYP2D6*1 and null alleles had a coefficient of variation (CV) of 43% and 56%, respectively. The variability of homozygotes of CYP2D6*2 and CYP2D6*10 was 63% and 66%, while that of the heterozygotes of CYP2D6*2 and null alleles and CYP2D6*10 and null alleles was 125% and 109%, respectively. Based on the variability and reported frequency of the CYP2D6 genotype in Asians and Caucasians, the inter-individual variability of CLint,h,2D6 of extensive metabolizers was estimated at 60 70%, which provided comparable variability of AUC with the literature values of DM, tolterodine, risperidone and atomoxetine. It is suggested that the produced inter-individual variability of CLint,h,2D6 in each genotype is useful for estimating AUC variability of the CYP2D6 substrates in the regional population.