Pharmacokinetics of cyproheptadine and its metabolites in rats.

To investigate the pharmacokinetics of cyproheptadine (CPH) and its metabolites, the plasma concentration and urinary excretion of CPH and its detectable metabolites were determined after intravenous (i.v.) administration of parent or synthesized metabolites to rats. The plasma CPH concentration-time course was subjected to biexponential calculation following the i.v. administration of CPH, producing the temporal and low plasma concentrations of desmethylcyproheptadine (DMCPH) and the sustained plasma concentrations of desmethylcyproheptadine-epoxide (DMCPHepo). DMCPH was also eliminated, according to the biexponential equation, after i.v. administration of performed DMCPH, forming DMCPHepo in plasma. On the other hand, no detectable DMCPHepo was found in plasma after the i.v. administration of cyproheptadine epoxide (CPHepo). All compounds administered had large distribution volumes and were almost entirely excreted as DMCPHepo in urine; this excretion continued for a long time. However, the urinary excretion pattern of DMCPHepo after CPHepo was different from those after CPH and DMCPH. The mean residence times of the epoxidized metabolites estimated from the urinary data were much longer than those from the plasma concentration data, suggesting either a gradual reflux of the metabolites from a tissue depot into systemic circulation under those plasma concentrations close of detection limit, or some interaction which delays excretion into the urine. This study suggests that both metabolic pathways of CPH, through DMCPH and CPHepo, to DMCPHepo are possible, but that the demethylation of CPH largely occurs prior to epoxidation; also that the extensive and persistent distribution of DMCPHepo to tissues may relate to the toxicity of CPH reported in rats.