Selectivity of omeprazole inhibition towards rat liver cytochromes P450

Abstract

1. The potency and selectivity of omeprazole as an inhibitor of cytochrome P450- mediated drug oxidations has been assessed in hepatic microsomes from the untreated, phenobarbitone-treated, beta -naphthoflavone-treated and dexamethasone-treated rat. Using the marker substrates diazepam, ethoxycoumarin, ethoxyresofurin and ethylmorphine in the above microsomal preparations, inhibitory activity against CYP1A, 2B, 2C and 3A members of the cytochrome P450 superfamily were determined. 2. In each situation studied the kinetics of inhibition by omeprazole were competitive in nature with Ki 's ranging from 25 to 1000 mu M. Marker activities for the 3A family in microsomes from the dexamethasone-treated and phenobarbitone-treated rat (3-hydroxylation of diazepam and N -demethylation of ethylmorphine) were most susceptible to omeprazole inhibition (Km Ki ratios greater than unity) compared with marker activities for the CYP1A, 2B and 2C sub-families (Km Ki ratios unity). 3. Omeprazole sulphoxide showed similar potency and selectivity of inhibition to its parent drug. Analogous studies with the same marker activities using ketoconazole indicated that both omeprazole andits sulphoxide metabolite are less potent as an inhibitor of cytochrome P4503A in rat than this well characterised prototype.