title: Inter-individual variability of in vivo CYP2D6 activity in different genotypes.
abstract: 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 (CL(int,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 CL(int,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 CL(int,h,2D6) in each genotype is useful for estimating AUC variability of the CYP2D6 substrates in the regional population.
authors.affiliation: Keio University, Tokyo, Japan. chiba-kj@pha.keio.ac.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Chiba
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
authors.forename: Toshio
authors.initials: T
authors.lastname: Suwa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D019540:Area Under Curve; D000069445:Atomoxetine Hydrochloride; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics; D003198:Computer Simulation; D003408:Cresols / Q000493:pharmacokinetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan / Q000493:pharmacokinetics; D005787:Gene Frequency; D014644:Genetic Variation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008657:Metabolic Clearance Rate; D008957:Models, Genetic; D009010:Monte Carlo Method; D010641:Phenotype; D010665:Phenylpropanolamine / Q000493:pharmacokinetics; D011437:Propylamines / Q000493:pharmacokinetics; D018967:Risperidone / Q000493:pharmacokinetics; D013379:Substrate Specificity; D000068737:Tolterodine Tartrate
chemical_list: D001559:Benzhydryl Compounds; D003408:Cresols; D011437:Propylamines; D010665:Phenylpropanolamine; D000069445:Atomoxetine Hydrochloride; D000068737:Tolterodine Tartrate; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone