QUINIDINE INHIBITION OF DEBRISOQUINE S(+)-4-HYDROXYLATIONS AND 7-HYDROXYLATIONS IN CHINESE OF DIFFERENT CYP2D6 GENOTYPES

Pronounced differences in the CYP2D6 gene between Chinese and Caucasians have previously been described. There was a low frequency of detrimental mutations in the Chinese CYP2D6 gene causing the poor metabolizer (PM) phenotype. In contrast to Caucasians where the Xba 1 44 kb allele is almost always associated with the PM phenotype, Chinese with the 44/44 kb RFLP pattern are extensive metabolizers (EM). In order to evaluate whether the debrisoquine hydroxylation seen in subjects with this haplotype is catalysed by a functionally similar enzyme to CYP2D6 or is catalysed by another type of P450 isozyme, product selectivity of the 4-hydroxylation was studied in 2 7 Chinese. The inhibition of CYP2D6 by quinidine was also investigated. In the 26 Chinese EM the S(+)-4-hydroxy enantiomer was found to be the major urinary metabolite of debrisoquine with an enantiomeric excess of 96.8-100%, which is similar to that in Caucasians. A correlation between the amount of S(+)-4-hydroxy and the minor 7-hydroxy metabolites excreted in urine (r = 0. 72; p < 0.00 1) was seen. The amount of these two metabolites excreted was less in Chinese EM of debrisoquine with the 44/44kb RFLP pattern, than in those with the wild type 29/29 kb pattern (p < 0.01). The stereoselectivity was very high in both groups. All Chinese homozygous for the 44 kb fragment (n = 5) were transformed to apparent PM after a single 100 mg dose of quinidine similarly to five Caucasian EM. Both the S(+)-4- and 7-hydroxylations of debrisoquine were inhibited by quinidine in both populations. This study shows that the cytochrome P450 catalysing the 4- and 7-hydroxylations of debrisoquine in Chinese EM has the same properties (product stereoselectivity and inhibition by quinidine) as the CYP2D6 in Caucasian EM.