title: Effect of levomepromazine and metabolites on debrisoquine hydroxylation in the rat.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Tromsø, Norway.
authors.forename: P A
authors.initials: PA
authors.lastname: Hals
authors.forename: S G
authors.initials: SG
authors.lastname: Dahl
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003647:Debrisoquin / Q000008:administration & dosage / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006900:Hydroxylation / Q000187:drug effects; D008297:Male; D008728:Methotrimeprazine / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004338:Drug Combinations; D003577:Cytochrome P-450 Enzyme System; D008728:Methotrimeprazine; D003647:Debrisoquin