In vitro metabolism of amiodarone by rabbit and rat liver and small intestine
Young, R.A.; Mehendale, H.M.
Drug Metabolism and Disposition the Biological Fate of Chemicals 14(4): 423-429
1986
ISSN/ISBN: 0090-9556 PMID: 2873989 Document Number: 281233
The present studies were designed to investigate whether aminodarone (Am) is metabolized in the major organs and tissues of the rat and rabbit. Incubations using Am and tissue homogenates (600 g supernatant) of rabbit and rat lung, liver, kidney, and gut revealed formation of desethylamiodarone (DEA) by the liver and gut. Subsequent experiments using the post-mitochondrial, cytosolic, and microsomal fractions of these tissues indicated that metabolism of Am was greatest in the microsomal fractions. In both species, greater DEA formation was detected for microsomes of hepatic origin. The hepatic microsomal mediated production of DEA was altered by protein concentration in both the rabbit and rat preparations with protein concentrations of 5 mg providing the greatest DEA production. DEA formation by gut microsomes was greatest at 3 mg of protein for the rabbit but exhibited no significant change from 1 mg to 10 mg of protein for the rat. In vitro metabolism of Am by rabbit and rat hepatic microsomal preparations was significantly reduced by 1 mM piperonyl butoxide, SKF 525-A, n-octylamine, and carbon monoxide. Effects of these inhibitors on rabbit and rat gut microsomal incubations were inconclusive. HPLC analysis of incubation samples revealed a species difference in the metabolism of Am as demonstrated by the detection of these metabolites in addition to DEA. The unidentified metabolites (I, II, III) were detected in rabbit hepatic microsomal incubations. Metabolite II was also detected in incubations using rabbit duodenal tissue microsomes. No metabolites other than DEA were found in incubations using rat tissues. Evidence for secondary biotransformation of DEA to metabolite I and tentative assignment of metabolite I as deiodinated DEA is presented. These studies indicate that significant metabolism of Am resides in the hepatic tissue of rabbits and rats, and that the metabolism is mediated by microsomal cytochrome P-450 activity.