Evidence that drug metabolites are involved in cyproheptadine-induced loss of pancreatic insulin.
The effects of pretreatment with inhibitors of drug metabolism on the biotransformation of cyproheptadine (CPH) and the ability of the drug to deplete pancreatic insulin were investigated. CPH (45 mg/kg p.o.) or water was given once daily for 2 days to rats. SKF-525A (beta-diethylaminoethyl-2,2-diphenylpentanoate) (40 mg/kg i.p.) or water was administered 0.5 hr before the CPH treatment, and the animals were sacrificed 6 hr after the second dose of CPH. The pancreatic insulin concentration was determined, and the levels of CPH and its metabolites in pancreas, liver and lung were measured. It was found that SKF-525A pretreatment significantly protected rats from the insulin loss induced by CPH; SKF-525A alone had no effect on pancreatic insulin. The tissues from animals pretreated with SKF-525A, when compared with those of the control, had 10-fold higher levels of CPH, significantly lower concentrations of the metabolite desmethylcyproheptadine-10,11-epoxide (DMCPH-epoxide) and no change in the levels of desmethylcyproheptadine (DMCPH). The in vivo N-demethylation of N-[methyl-14C]CPH, as measured by the excretion rate of 14CO2, also was inhibited by SKF-525A pretreatment. Similar experiments were performed with another inhibitor of drug metabolism, 3,5-diethoxycarbonyl-2,6-dimethyl-4-ethyl-1,4-dihydropyridine (DDEP, 50 mg/kg i.p.); and the same results were obtained. In other experiments using DMCPH as the insulin-depleting compound, SKF-525A or DDEP pretreatment also afforded significant protection against chemical-induced insulin loss.(ABSTRACT TRUNCATED AT 250 WORDS)
Chow
S A
SA
Department of Pharmacology, College of Medicine, University of Iowa, Iowa City.
Rickert
D E
DE
Fischer
L J
LJ
D000818:Animals; D003533:Cyproheptadine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011739:Pyrimethamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D007328:Insulin; D011725:Pyridines; C037546:desmethylcyproheptadine; C013109:metapyrone; D003533:Cyproheptadine; C013909:etoprine; D011739:Pyrimethamine