POSTNATAL CHANGES IN THE INSULIN-DEPLETING ACTION AND DISPOSITION OF CYPROHEPTADINE IN RATS

The relationship between age-related differences in cyproheptadine (CPH)-induced alteration of endocrine pancreas function and the disposition of the drug was examined in this study. Various doses of CPH (5, 11, 22.5 or 45 mg/kg) were given orally once daily for 2 days to 10-, 15-, 25- and 50-day-old rats. Pancreatic and serum insulin measured 24 h after the second dose showed a drug-dependent decline, and the extent of this effect was dependent on the dose administered and the age of the animal. In 50-day-old rats, a significant reduction in pancreatic and serum insulin was detected only after high doses (22.5 and 45 mg/kg) of the drug. However, in 10- and 15-day-old rats, the effects were observed after the lowest dose (5 mg/kg). In separate experiments, the concentrations of CPH and its active metabolites, desmethylcyproheptadine (DMCPH), desmethylcyproheptadine-10,11-epoxide (DMCPH-epoxide) and cyproheptadine-10,11-epoxide (CPH-epoxide), were measured in the pancreas, liver and lung of neonatal and young rats at various times after the second dose of CPH (11 mg/kg). In the younger age groups (10- and 15-day-olds), there were significantly higher tissue levels of unchanged drug at all times examined. Certain of the drug metabolites known to be inhibitors of insulin synthesis had higher and/or more prolonged tissue concentrations in younger animals. For example, the metabolite CPH-epoxide was found only in tissues from younger age groups. Twenty-four hours after the second dose of CPH, no drug-derived product was present in tissues of 25- and 50-day-old rats, whereas significant amounts of DMCPH-epoxide, a potent CPH metabolite inhibiting insulin synthesis, was detected in the tissues of 10- and 15-day-old rats. The data show that there are age-related differences in the susceptibility of pancreatic B cells to the actions of CPH, and that these differences are associated with age-related changes in the disposition of the drug.