THE TISSUE DISTRIBUTION OF CYPROHEPTADINE AND ITS METABOLITES IN RATS AND MICE

¹ Center for Biochemical Pharmacology and Toxicology, Department of Pharmacology, College of Medicine, University of Iowa, Iowa City, Iowa

The tissue distribution of unchanged drug and metabolites was studied in rats and mice given p.o. doses of ¹⁴C-cyproheptadine (CPH) in an effort to determine if there is a species difference in CPH disposition that correlates with the species difference in the production of pancreatic islet cell lesions by CPH. The tissue concentration of CPH-related substances was determined by measurement of radioactivity. A gas chromatographic method was developed for the analysis of CPH and a metabolite, desmethylcyproheptadine in tissues. The difference between the concentration of these two compounds and the total tissue radioactivity was designated as "other metabolites" (OM) and represented unidentified metabolites of CPH. After a p.o. dose, unchanged CPH and the metabolite desmethylcyproheptadine decreased relatively rapidly in rat tissues. The majority of the radioactivity in the kidney, liver and pancreas of the rat, as early as three hours after the dose, consisted of OM (unidentified metabolites) and at six hours the OM component comprised the majority of CPH-related compounds in all rat tissues except the brain. In contrast, the OM fraction did not accumulate in mouse tissues. After six hours it was detectable only in trace amounts in mouse kidney, lung, pancreas, brain and small intestine. The major component present at all times in most mouse tissues was desmethylcyproheptadine. The data show that there is a marked difference in CPH disposition between rats and mice. A relationship between CPH metabolism and the production of beta cell damage is suggested since we have previously found that the rat, but not the mouse, is susceptible to the pancreatic toxicity of the drug.