Tissue metabolites of trifluorperazine, fluphenazine, prochlorperazine, and perphenazine. Kinetics in chronic treatment.

Repeated oral treatment of male rats with piperazine-substituted phenothiazine drugs in doses of 25 mg/kg or more daily led to an accumulation of metabolites containing an ethylenediamine group instead of the piperazine ring. These products of ring degradation with and without removal of the N-alkyl group were found, together with the parent drugs and their N-dealkylated metabolites, in liver, lung, kidney, and spleen, as well as in brain when high doses were administered. After termination of treatment, the ethylenediamine derivatives were eliminated more slowly than were their congeners containing the intact piperazine ring. Parallel observations were made in dogs given fluphenazine in daily doses of up to 40 mg/kg. Quantitative differences were observed in the relative amounts of mono- and disubstituted ethylenediamine metabolites accumulated in rat tissues during treatment with the various drugs; the proportion of the monosubstituted product formed by N-dealkylation and ring cleavage declined in the following order: perazine, prochlorperazine, trifluoperazine, fluphenazine, perphenazine. Condensation products of the ethylenediamine derivatives with formaldehyde were split in the extraction procedure used.