Comparative inhibitory effects of mefloquine and primaquine on hepatic drug-metabolizing enzymes

Abstract

The effect of mefloquine (MQ) on hepatic drugmetabolizing enzymes in the rat had been comapred with that of primaquine (PQ) both in vitro and in vivo. For in vitro studies using type I compounds (aminopyrine and hexobarbital), it was found that MQ inhibited only aminopyrine N-demethylase whereas PQ inhibited both aminopyrine N-demethylase and hexobarbital oxidase. At the concentration of 10(4) M these two antimalarials produced comparable per cent inhibition (approximately 54%) on aminopyrine N-demethylase, while at the lower concentration PQ produced greater inhibition than MQ. As for type II compouds (aniline and p-chloro-N-methylaniline), MQ exerted a very weak inhibitory effect on aniline hydroxylase (23% at 10(-4)M but had no effect on p-chloro-N-methylaniline N-demethylase. On the contrary, PQ was found to be quite a potent inhibitor of anilline hydroxylase but to be a very weak inhibitor of p-chloro-N-methylanline N-demethylase (11% at 10(-4)M). For a reverse type I compound, p-nitroanisole, both MQ and PQ could inhigit the enzyme p-nitroanisloe-O-demethylase, though MQ was a very weak inhibitor. Kinetic studies shiwed that aminopyrine N-demethylase was inhibited noncompetitively by MQ whereas th einhibition by PQ was competitive. PQ was also found to be a noncompetitive inhibitor of hexobarbital oxidase, whilc producing a noncompetitive and competitive inhibition on aniline hydroxylase and p-chloro-N-methylaniline N-demethylase, respectively. the kinetic nature of inhibition by both MQ and PQ on the metabolism of the reverse type I compound was noncom-petitive. The results from studies in vivo were consistent with the in vitro findings. PQ (50 mg/kg, IP) was found to prolong zoxazolamine paralysis time while MQ (50mg/kg, PO) had no effect. These findings thus demonstrate that MQ is a much weaker inhibitor of hepatic drug-matabolizing enzymes than PQ.