Metabolism and disposition of cyproheptadine and desmethylcyproheptadine in pregnant and fetal rats.

The tissue distribution of unchanged drug and metabolites in pregnant rats was studied following oral administration of cyproheptadine (CPH) or its N-demethylated metabolite, desmethylcyproheptadine (DMCPH). A high performance liquid chromatographic (HPLC) method was developed for analysis of CPH and its metabolites in maternal and fetal tissues. In pregnant rats given CPH (11 mg/kg) during the final 2 or 8 days of gestation, the unchanged drug, DMCPH and desmethylcyproheptadine-10,11-epoxide (DMCPH-epoxide) were detected in various maternal and fetal tissues, including pancreas, liver, lung, kidney and placenta. DMCPH and DMCPH-epoxide were also present in fetal tissues after 8 oral doses of DMCPH (11 mg/kg) to pregnant rats. Tissue concentrations of unchanged CPH and its metabolites, after each treatment regimen, were highest in the lung. Except for pancreas and brain, the levels of CPH, DMCPH, or DMCPH-epoxide in tissues at early times after completing CPH treatment were 3- to 10-fold higher in the dam than in the fetus. Brain levels of CPH metabolites were higher in the fetus than in the maternal animal. The metabolite DMCPH-epoxide appeared in fetal pancreas in concentrations equal to those in the maternal pancreas. In separate experiments designed to examine the metabolic capability of the fetus (day 20 of gestation), it was found that fetally administered CPH was not demethylated and, instead, epoxidated to form cyproheptadine-10,11-epoxide (CPH-epoxide). Administration of the metabolite DMCPH to the fetus showed that it was also readily converted to an epoxide.(ABSTRACT TRUNCATED AT 250 WORDS)