DMD Noab BioDiscoveries - Shaping Drug Discovery

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on October 4, 2005; DOI: 10.1124/dmd.105.006742

0090-9556/06/3401-43-50$20.00
DMD 34:43-50, 2006

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.105.006742v1
34/1/43    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shayeganpour, A.
Right arrow Articles by Brocks, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shayeganpour, A.
Right arrow Articles by Brocks, D. R.

DETERMINATION OF THE ENZYME(S) INVOLVED IN THE METABOLISM OF AMIODARONE IN LIVER AND INTESTINE OF RAT: THE CONTRIBUTION OF CYTOCHROME P450 3A ISOFORMS

Anooshirvan Shayeganpour, Ayman O. S. El-Kadi, and Dion R. Brocks

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada

In humans, cytochrome P450 3A (CYP3A4) is a major enzyme involved in the metabolism of amiodarone (AM) to its major metabolite, desethylamiodarone (DEA). In rat, a commonly used animal model, metabolism of AM has not been well studied. To determine whether DEA is formed by CYP3A isoenzymes in the rat, microsomal protein was harvested from liver and intestine of male Sprague-Dawley rats. The metabolism of AM in each tissue was assessed utilizing chemical and immunological inhibitors. Ketoconazole, a presumed inhibitor of CYP3A1/2, significantly inhibited formation of DEA by hepatic and intestinal microsomes. However, based on the DEA formation kinetics in both microsomal preparations, it appeared that more than one cytochrome P450 enzyme was involved in the process. Coincubation of AM with microsomes and anti-CYP3A2 confirmed the role of CYP3A2 in the metabolism of AM in liver. DEA was also formed by rat recombinant CYP1A1 and CYP3A1, and was inhibited by ketoconazole; hence the participation of these enzymes in the intestinal DEA formation is likely. However, anti-CYP2B1/2 or -CYP1A2 antibodies had no effect on DEA formation. In rats given oral or intravenous AM, oral ketoconazole caused significant increases in area under the concentration versus time curve (AUC) of oral and i.v. treated rats and greater than 50% decreases in the total body clearance and Vdss of i.v. treated rats. Although low to undetectable concentrations of DEA were a limitation for determination of AUC of DEA in vivo, it was confirmed that ketoconazole could cause a significant increase in AM concentrations in rat.

Address correspondence to: Dr. Dion R. Brocks, Associate Professor, Faculty of Pharmacy and Pharmaceutical Sciences, 3118 Dentistry/Pharmacy Centre, University of Alberta, Edmonton, AB, Canada T6G 2N8. E-mail: dbrocks{at}pharmacy.ualberta.ca




This article has been cited by other articles:


Home page
 Toxicol SciHome page
H. M. Korashy, A. Shayeganpour, D. R. Brocks, and A. O.S. El-Kadi
Induction of Cytochrome P450 1A1 by Ketoconazole and Itraconazole but not Fluconazole in Murine and Human Hepatoma Cell Lines
Toxicol. Sci., May 1, 2007; 97(1): 32 - 43.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
G. Lin, J. Tang, X. Q. Liu, Y. Jiang, and J. Zheng
Deacetylclivorine: A Gender-Selective Metabolite of Clivorine Formed in Female Sprague-Dawley Rat Liver Microsomes
Drug Metab. Dispos., April 1, 2007; 35(4): 607 - 613.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.