INHIBITION OF THE SULFOXIDATION OF OMEPRAZOLE BY KETOCONAZOLE IN POORAND EXTENSIVE METABOLIZERS OF S-MEPHENYTOIN

Background: The metabolism of omeprazole includes hydroxylation cataly zed by CYP2C19 and, to a minor extent, sulfoxidation, presumably by CY P3A4. Sulfoxidation may be the predominant pathway in individuals devo id of the genetically determined CYP2C19 activity. Ketoconazole is a k nown CYP3A4 inhibitor in daily doses from 200 to 400 mg, In this study ketoconazole was used as a probe to investigate the extent to which C YP3A4 is involved in omeprazole metabolism in vivo. Methods: A single oral 20 mg dose of omeprazole before and after four daily doses of 200 , 100, or 50 mg ketoconazole was given to 10 healthy subjects, previou sly phenotyped as poor or extensive metabolizers of S-mephenytoin. Con centrations of omeprazole, 5-hydroxyomeprazole, omeprazole sulfone, an d ketoconazole were analyzed with, reversed-phase HPLC methods in plas ma samples collected repeatedly for 12 hours after dosing. Results: Af ter intake of 20 mg omeprazole with 0, 50, 100, and 200 mg ketoconazol e, mean values for omeprazole sulfone area under the plasma concentrat ion versus time curve from 0 to 6 hours [AUC(0-6)] were 482, 206, 167, and <100 nmol/L . hr in extensive metabolizers and 3160, 2430, 937, a nd 534 nmol/L . hr in poor metabolizers, respectively. Mean omeprazole AUC(0-6) increased from 1660 to 2265 nmol/L . hr in extensive metabol izers and from 7715 to 15319 nmol/L . hr in poor metabolizers after in take of 200 mg ketoconazole. Conclusions: An oral daily dose of 100 to 200 mg ketoconazole is sufficient to provide a marked inhibition of t he formation of the omeprazole: sulfone in both extensive and poor met abolizers and leads to a doubling of omeprazole levels in poor metabol izers, whereas 50 mg ketoconazole provides only partial inhibition, We concluded that CYP3A4-catalyzes the sulfoxidation of omeprazole and t hat this is the predominant metabolic pathway of omeprazole in poor me tabolizers of S-mephenytoin.