In vitro effects of racemates, separate enantiomers and major metabolites of mefloquine and halofantrine on metoprolol biotransformation by rat liver microsomes

1. The effects of the anti-malarial drugs mefloquine and halofantrine and of their major metabolites on metoprolol metabolism by rat liver microsomes have been investigated. 2. The observed K-m and V-max, and the formation kinetics of alpha-hydroxymetoprolol and O-demethylmetoprolol, two major metoprolol metabolites, were in keeping with published data. 3. In vitro, mefloquine competitively inhibited metoprolol biotransformation, whereas halofantrine did so in a mixed fashion. The mefloquine K-i of metoprolol alpha-hydroxplation and O-demethylation were 3.4 and 5.8 mu M respectively, whereas those of halofantrine were 0.15 and 0.32 mu M respectively. 4. The main metabolites, N-debutylhalofantrine and carboxymefloquine, were 4-10-fold less inhibitory than the parent drugs. The difference in inhibitory potency of parent drugs and metabolites was higher for halofantrine than for mefloquine. The potency order for metoprolol metabolism inhibition was halofantrine much greater than mefloquine = N-debutylhalofantrine > carboxymefloquine. 5. A preliminary study with anti-malarial enantiomers showed a weak difference, in metoprolol metabolism inhibition between the enantiomers of halofantrine or mefloquine. 6. It is concluded that halofantrine is a potent inhibitor of metoprolol metabolism and that halofantrine metabolites or its enantiomers may have a different inhibitor potency than the parent drug: (1) the inhibition potency of these compounds should be studied in vitro and (2) their in vivo elimination half-life and plasma concentrations should be taken into be account to extrapolate this experimental results to in vivo.