Vol. 280, Issue 2, 730-738, 1997

Inhibition by Omeprazole of Proguanil Metabolism: Mechanism of the Interaction In Vitro and Prediction of In Vivo Results from the In Vitro Experiments¹

Christian Funck-Brentano, Laurent Becquemont, Anne Leneveu, Annie Roux, Patrice Jaillon and Philippe Beaune

Clinical Pharmacology Unit, Saint-Antoine University Hospital-School of Medicine, Paris, France (C.F.-B., P.J.), Unité INSERM U75, Faculté de Médecine Necker-Enfants Malades, Paris, France (L.B., P.B.), and Laboratoire de Toxicologie et de Pharmacocinétique, CHU Ambroise Paré, Boulogne, France (A.L., A.R.)

Both the antimalarial prodrug proguanil and the gastric proton pump inhibitor omeprazole are substrates for cytochrome P450 (CYP)2C19 and CYP3A. However, the relative contribution of each enzyme to proguanil bioactivation to cycloguanil and to the metabolism of omeprazole, as well as their potential to interact, remains to be examined. The bioactivation of proguanil to its active metabolite cycloguanil was studied in vitro in human liver microsomes and in vivo in 12 healthy subjects, in the absence and in the presence of omeprazole. The formation of cycloguanil from proguanil exhibited biphasic kinetic behavior in four of six human livers, indicating that at least two enzymes are responsible for this metabolic step. Cycloguanil formation activity did not correlate with immunoreactive CYP3A4 content or with CYP3A4 activity, as measured by testosterone 6-hydroxylation, suggesting that CYP3A4 plays a limited role in cycloguanil formation. Furthermore, troleandomycin (10 µM) inhibited only 10 to 17% of cycloguanil formation at proguanil concentrations of 100 and 500 µM. At a proguanil concentration of 20 µM, omeprazole at 10 µM inhibited cycloguanil formation in vitro by 47 ± 59%. These in vitro results were consistent with the results of our in vivo study in healthy subjects, which showed a 32 ± 11% decrease in proguanil apparent oral clearance and a 65 ± 8% decrease in proguanil partial metabolic clearance to cycloguanil in the presence of omeprazole (both P < .001). We conclude that in vitro studies of proguanil metabolism and interactions are predictive of in vivo situations, that CYP2C19 is the main enzyme responsible for proguanil bioactivation to cycloguanil and that omeprazole inhibits this biotransformation in vitro and in vivo by inhibiting this enzyme.