Bioinformatics research on inter-racial difference in drug metabolism I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19.

The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. In the present study, the frequencies of mutant alleles and PMs in each race were analyzed based on information from published studies, considering the genetic polymorphisms of CYP2D6 and CYP2C19 as the causal factors of racial and inter-individual differences in pharmacokinetics. As a result, it was shown that there were racial differences in the frequencies of each mutant allele and PMs. The frequencies of PMs on CYP2D6 are 1.9% of Asians and 7.7% of Caucasians, and those of PMs on CYP2C19 are 15.8% of Asians and 2.2% of Caucasians. Based on the results, it was suggested that there would be racial differences in the frequencies of PM subjects whose blood concentrations might be higher for drugs metabolized by these enzymes. Additionally, it was suggested that enzyme activities would vary according to the number of functional alleles even in subjects judged to be extensive metabolizers (EMs). In the bridging study, genetic information regarding CYP2D6 and CYP2C19 of the subjects will help extrapolate foreign clinical data to a domestic population.

Bioinformatics research on inter-racial difference in drug metabolism II. Analysis on relationship between enzyme activities of CYP2D6 and CYP2C19 and their relevant genotypes.

The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. We have analyzed frequencies of mutant alleles and PMs based on the published data in previous study (Shimizu, T. et al.: Bioinformatics research on inter-racial difference in drug metabolism, I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19.). The study shows that there were racial differences in the frequencies of each mutant allele and PMs. In the present study, the correlation between genotypes and drug-metabolizing enzyme activities was investigated. The result showed that enzyme activities varied according to the genotypes of subjects even in the same race. On the other hand, if subjects had the same genotypes, almost no racial differences were observed in drug-metabolizing enzyme activities. From these results, it was supposed that the racial differences in activities of these enzymes could be explained by the differences in distribution of genotypes. It would be possible to explain the racial differences in drug-metabolizing enzyme activities based on the differences on individual pharmacogenetic background information, not merely by comparison of frameworks such as races and nations.