Inter-individual Variability of In Vivo CYP2D6 Activity in Different Genotypes
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- CHIBA Koji
- Keio University
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- KATO Motohiro
- Chugai Pharmaceutical Co. Ltd.
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- ITO Takashi
- Daiichi Sankyo Co. Ltd.
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- SUWA Toshio
- Keio University
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- SUGIYAMA Yuichi
- The University of Tokyo
書誌事項
- タイトル別名
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- Inter-individual Variability of <i>In Vivo</i> CYP2D6 Activity in Different Genotypes
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説明
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.<br>
収録刊行物
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- Ｄｒｕｇ Ｍｅｔａｂｏｌｉｓｍ ａｎｄ Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ
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Ｄｒｕｇ Ｍｅｔａｂｏｌｉｓｍ ａｎｄ Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ 27 (4), 405-413, 2012
日本薬物動態学会