Document Detail


Biotransformation of tipredane, a novel topical steroid, in mouse, rat, and human liver homogenates.
MedLine Citation:
PMID:  2573497     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The in vitro biotransformation pathways of 3H-tipredane (3H-TP) were studied. 3H-TP, at concentrations of 1 and 250 microM, was incubated with the 10,000g supernatant fraction of the liver homogenates of mice, rats, and one human. The incubation mixtures were deproteinated with methanol and, after removal of methanol by evaporation, extracted with dichloromethane. The dichloromethane extracts were then fractionated by HPLC. 3H-TP was extensively biotransformed by the liver homogenates of the three species studied; 17 metabolites were isolated and characterized by their retention times on HPLC compared to those of the reference standards. Fourteen metabolites were identified using MS and, for some, NMR spectroscopy. Three major biotransformation pathways of TP were identified: 1) sulfoxidation, 2) elimination of the alkylthio groups, and 3) hydroxylation of the steroid nucleus. Combinations of these processes and subsequent reactions resulted in the formation of numerous metabolites whose biological activities were significantly less than that of TP. The separation of local anti-inflammatory activity from systemic side effects observed for TP in animals and humans is most probably due to its metabolic inactivation, primarily in the liver.
Authors:
S J Lan; L M Scanlan; S H Weinstein; R K Varma; B M Warrack; S E Unger; M A Porubcan; B H Migdalof
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  17     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:    1989 Sep-Oct
Date Detail:
Created Date:  1989-12-29     Completed Date:  1989-12-29     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  532-41     Citation Subset:  IM    
Affiliation:
Squibb Institute for Medical Research, Princeton, NJ 08543-4000.
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MeSH Terms
Descriptor/Qualifier:
Administration, Topical
Androstadienes / pharmacokinetics*
Animals
Anti-Inflammatory Agents / pharmacokinetics*
Biotransformation / drug effects
Chromatography, High Pressure Liquid
Humans
Liver / drug effects,  metabolism*
Mass Spectrometry
Mice
Models, Biological
Rats
Rats, Inbred Strains
Sulfoxides / pharmacokinetics
Chemical
Reg. No./Substance:
0/Androstadienes; 0/Anti-Inflammatory Agents; 0/Sulfoxides; 85197-77-9/tipredane

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


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