Metabolism of trifluoperazine, fluphenazine, prochlorperazine and perphenazine in rats: In vitro and urinary metabolites

Abstract

In vitro and in vivo metabolites of trifluoperazine, fluphenazine, prochlorperazine and perphenazine were isolated by solvent extraction and thin layer chromatography and quantified by u.v. spectroscopy. In liver microsomes from male rats all four drugs underwent N-dealkylation. N-oxidation, sulfoxidation and aromatic hydroxylation. The relative rates of these reactions depended on the substrate concentration, N-oxidation being favoured at higher concentrations. N-Demethylation of trifluoperazine proceeded faster than removal of the hydroxyethyl group from fluphenazine which led to the same metabolite N[γ-(2-trifluoromethyl-phenothiazinyl-10)-propyl] piperazine. The same applied to the dealkylation of prochlorperazine and perphenazine. Following oral administration of 10 mg/kg of the drugs, male rats excreted 1.8-4 per cent of the dose within the first 12 hr in urine in the form of the sulfoxide and the N-dealkylated sulfoxide. In vivo, too, the N-hydroxyethyl group was removed to a smaller extent than the N-methyl group. N-Oxides were not detected in urine at this dose level, but when 25 or 50 mg/kg prochlorperazine were administered, rats excreted small amounts of the N-oxide. © 1974.