Effect of levomepromazine and metabolites on debrisoquine hydroxylation in the rat.

The influence of the major metabolites of the phenothiazine derivative, levomepromazine (methotrimeprazine), on hydroxylation of debrisoquine was examined in male Sprague-Dawley rats. The metabolic ratio of debrisoquine/4-hydroxy debrisoquine was first determined in rats after oral administration of 10 mg/kg of debrisoquine. Then the same dose of debrisoquine was co-administered with various doses of levomepromazine or one of its metabolites. Levomepromazine and its sulphoxidated, N-demethylated and O-demethylated metabolites caused highly significant and dose-dependent increases in the debrisoquine metabolic ratio. 3-Hydroxy levomepromazine had no significant effect on the metabolism of debrisoquine. This indicates that the non-hydroxylated metabolites of levomepromazine have relatively high affinities for the cytochrome P450 enzyme which converts debrisoquine to 4-hydroxy debrisoquine in the rat. Such metabolites may therefore be responsible for a considerable part of the inhibitory effect of debrisoquine hydroxylation previously reported in patients treated with phenothiazine neuroleptics.