Received for publication August 5, 2005.
Revised September 29, 2005.
Accepted for publication September 30, 2005.

Determination of the enzyme(s) involved in the metabolism of amiodarone in liver and intestine of rat: The contribution of cytochrome P-450 3A isoforms

Abstract

In humans, cytochrome p-450 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 if 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 CYP enzyme was involved in the process. Co-incubation 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 were 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 AUC of oral and i.v. treated rats and over 50% decreases in the CL 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.

Key words: CYP1A, CYP2B, CYP3A, cytochrome P450, drug interactions, enzyme inhibitors, inhibition, liver microsomes, microsomes, pharmacokinetics

This article has been cited by other articles:

				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]

				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]