DEBRISOQUINE AND MEPHENYTOIN OXIDATION IN SINHALESE - A POPULATION STUDY

The frequency distributions of the 0-8 h urinary metabolic ratios of d ebrisoquine and mephenytoin were measured in 111 healthy, unrelated Si nhalese resident in Sri Lanka. Blood samples were taken from 77 of the se subjects for CYP2D6 genotyping. Bimodality in the distribution of t he log(10) debrisoquine/4-hydroxydebrisoquine ratio was not evident fr om visual inspection and by kernel density analysis. The results of ge notyping indicated that 82% of the population were either homozygous f or the wild-type CYP2D6 gene or heterozygous for the wild type allele and the whole gene deletion. Eighteen per cent of the Sinhalese popula tion were heterozygous for the CYP2D6B mutation and the wild-type alle le. All of these genotypes give rise to the extensive metaboliser phen otype in white Caucasians. No CYP2D6A mutations were identified and no individuals who were homozygous for the mutant alleles were detected, which is in accord with an absence of phenotypic poor metabolisers of debrisoquine. The mutant CYP2D6 allele frequency in Sinhalese (9%) is only half that observed in white Caucasians. The S/R-mephenytoin rati o ranged from 0.09 to 2.27 (median 0.38). By visual inspection and ker nel density analysis the distribution of the S/R-mephenytoin ratio was bimodal and, using a value of 0.9 for the antimode, 16 (14%) subjects were poor metabolisers. In conclusion, the prevalence of the poor met aboliser phenotype in Sinhalese appears much lower for debrisoquine an d higher for mephenytoin than in white Caucasians. These findings are similar to those observed in Indians living in Bombay and in Oriental populations.