THE HYDROXYLATION OF OMEPRAZOLE CORRELATES WITH S-MEPHENYTOIN AND PROGUANIL METABOLISM

Objectives: This pharmacogenetic study was aimed at studying the patte rn of oxidation of omeprazole in a Turkish population and testing whet her omeprazole metabolism cosegregates with the genetically determined metabolism of mephenytoin and proguanil in Turkish subjects. Methods: The hydroxylation of omeprazole was measured in 116 unrelated healthy Turkish subjects after administration of a single oral dose of omepra zole (20 mg), using the ratio of omeprazole to 5-hydroxy-omeprazole in plasma 3 h after dosing. To 31 subjects, who were phenotyped with ome prazole, mephenytoin (100 mg, p.o.) or proguanil (200 mg, p.o.) were a dministered at least 1 week apart. The S/R ratio of mephenytoin and th e ratio of proguanil to cycloguanil were determined from an 8-h urine collection. Results: Based on the distribution of the log (omeprazole/ hydroxyomeprazole) values and using the antimode value of 0.8, the fre quency of poor metabolizers of omeprazole was estimated to be 7.7% (95 % confidence interval 3-18%) which was similar to that in the other Ca ucasian populations (P = 0.54: Fisher's exact test). Three poor metabo lizers of omeprazole were also classified as poor metabolizers of both mephenytoin and proguanil and no misclassification occurred with thre e phenotyping methods. All three methods separated poor or extensive m etabolizer phenotypes with complete concordance. The ratio of omeprazo le to hydroxyomeprazole correlated with the S/R ratio of mephenytoin a nd the ratio of proguanil to cycloguanil. Conclusion: These results su pport the hypothesis that the oxidative metabolism of three different drugs may be catalyzed by the same cytochrome P450 enzyme.