Inter-individual variability of in vivo CYP2D6 activity in different genotypes.

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.