Effect of mefloquine on hepatic drug metabolism in the rat: comparative study with primaquine.

The effect of the new antimalarial drug mefloquine (MQ) on hepatic drug metabolism in the rat has been studied in vitro and in vivo using three different substrates, aminopyrine, ethinyloestradiol and tolbutamide. Comparative studies have been performed with primaquine (PQ). In vitro, both MQ and PQ inhibited aminopyrine N-demethylase activity and the concentration required to produce 50% inhibition was 0.2 mM for MQ and approximately 0.1 mM for PQ. Lineweaver-Burk plots indicated inhibition by both antimalarials to be non-competitive. Both MQ and PQ produced comparable inhibition of ethinyloestradiol metabolism in vitro with the percentage recovery of the major metabolite, 2-hydroxyethinyloestradiol being reduced from 49.3 +/- 10.8 to 5.1 +/- 3.1 (0.5 mM MQ) and 1.5 +/- 0.4% (0.5 mM PQ, mean +/- S.D.). Following acute administration of MQ and PQ to rats (25 mg kg-1) recovery of hydroxytolbutamide the major metabolite of tolbutamide, was reduced. In the period 0-8 hr, MQ caused a reduction in recovery from 54.4 +/- 3.1 to 9.3 +/- 3.4% and PQ from the control level to 32.2 +/- 14.1%. There is therefore clear evidence that MQ inhibits hepatic microsomal enzymes both in vitro and in vivo. The more pronounced effect of MQ in vivo, in comparison with PQ, is probably a reflection of differences in the kinetics of the two antimalarials. The range of substrates studied indicate a non-selective and widespread inhibitory effect of these drugs on oxidative enzymes.