Document Detail


Postnatal changes in the insulin-depleting action and disposition of cyproheptadine in rats.
MedLine Citation:
PMID:  1914789     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
S A Chow; L J Fischer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Developmental pharmacology and therapeutics     Volume:  16     ISSN:  0379-8305     ISO Abbreviation:  Dev Pharmacol Ther     Publication Date:  1991  
Date Detail:
Created Date:  1991-11-01     Completed Date:  1991-11-01     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8003947     Medline TA:  Dev Pharmacol Ther     Country:  SWITZERLAND    
Other Details:
Languages:  eng     Pagination:  150-63     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, College of Medicine, University of Iowa.
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MeSH Terms
Descriptor/Qualifier:
Age Factors
Animals
Animals, Newborn
Cyproheptadine / pharmacokinetics,  pharmacology*
Dose-Response Relationship, Drug
Insulin / blood
Insulin Antagonists / pharmacokinetics,  pharmacology*
Islets of Langerhans / drug effects
Rats
Rats, Inbred Strains
Tissue Distribution
Grant Support
ID/Acronym/Agency:
AM25295/AM/NIADDK NIH HHS; GM12675/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Insulin Antagonists; 11061-68-0/Insulin; 129-03-3/Cyproheptadine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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