INHIBITION BY OMEPRAZOLE OF PROGUANIL METABOLISM - MECHANISM OF THE INTERACTION IN-VITRO AND PREDICTION OF IN-VIVO RESULTS FROM THE IN-VITRO EXPERIMENTS

Both the antimalarial prodrug proguanil and the gastric proton pump in hibitor omeprazole are substrates for cytochrome P450 (CYP)2C19 and CY P3A. However, the relative contribution of each enzyme to proguanil bi oactivation to cycloguanil and to the metabolism of omeprazole, as wel l as their potential to interact, remains to be examined. The bioactiv ation of proguanil to its active metabolite cycloguanil was studied in vitro in human liver microsomes and in vivo in 12 healthy subjects, i n the absence and in the presence of omeprazole. The formation of cycl oguanil 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 corre late with immunoreactive CYP3A4 content or with CYP3A4 activity, as me asured by testosterone 6 beta-hydroxylation, suggesting that CYP3A4 pl ays a limited role in cycloguanil formation. Furthermore, troleandomyc in (10 mu M) inhibited only 10 to 17% of cycloguanil formation at prog uanil concentrations of 100 and 500 mu M. At a proguanil concentration of 20 mu M, omeprazole at 10 mu M inhibited cycloguanil formation in vitro by 47 +/- 59%. These in vitro results were consistent with the r esults of our in vivo study in healthy subjects, which showed a 32 +/- 11% decrease in proguanil apparent oral clearance and a 65 +/- 8% dec rease in proguanil partial metabolic clearance to cycloguanil in the p resence of omeprazole (both P <.001). We conclude that in vitro studie s of proguanil metabolism and interactions are predictive of in vivo s ituations, that CYP2C19 is the main enzyme responsible for proguanil b ioactivation to cycloguanil and that omeprazole inhibits this biotrans formation in vitro and in vivo by inhibiting this enzyme.