BANTU TANZANIANS HAVE A DECREASED CAPACITY TO METABOLIZE OMEPRAZOLE AND MEPHENYTOIN IN RELATION TO THEIR CYP2C19 GENOTYPE

Objective: To investigate the CYP2C19 polymorphism in Tanzanians becau se this enzyme shows large interindividual differences in activity and metabolizes several drugs of importance in Africa, especially the ant imalarial agent chloroguanide (INN, proguanil). Methods: Two hundred f ifty-one Tanzanian healthy volunteers were phenotyped with respect to CYP2C19 with use of a single oral dose of mephenytoin (n = 106), a sin gle oral dose of omeprazole (n = 207), or both. Sixty-two were phenoty ped with both probe drugs. The urinary 0- to 8-hour S/R-mephenytoin ra tio and the plasma omeprazole metabolic ratio (MR) (omeprazole/hydroxy omeprazole) 3 hours after drug intake were determined. The genotype wa s determined by analysis for CYP2C191 (wt), CYP2C19*2 (ml), and CYP2C 293 (mz). Ten subjects with high omeprazole MR were screened for new mutations in the CYP2C19 gene by searching for single-strand conformat ion polymorphisms (SSCP). Results: Eight subjects were classified as m ephenytoin poor metabolizers (7.5%). Only 5 of these were homozygous f or mutated alleles. The S/R ratio was skewed to the right (lower CYP2C 19 activity) compared with other ethnic groups studied previously. No new mutations were found with polymerase chain reaction (PCR)-SSCP. We found 30 volunteers (14.5%) with an MR >7, which is the antimode foun d previously in white subjects and Asian subjects. Of the 251 voluntee rs genotyped, 3.2% were homozygous for mutated alleles and 66.1% were homozygous for the wild-type allele, The allele frequencies of CYP2C19 1, *2, and *3 were 81.5%, 17.9%, and 0.6%, respectively. The correlat ion between the S/R mephenytoin ratio and the omeprazole MR was signif icant (Spearman r = 0.59; P <.01), Conclusion: Tanzanians have a decre ased capacity to metabolize both omeprazole and mephenytoin when their genotype is compared with metabolic capacity and genotype in other pr eviously studied populations. We identified a low frequency of the Asi an allele (CYP2C193). Although we did not find any new mutations, our results may be consistent with the presence of yet-unidentified mutat ions of CYP2C19 that causes decreased CYP2C19 activity in the Tanzania n population.