title: The inhibitory effect of amiodarone and desethylamiodarone on dextromethorphan O-demethylation in human and rat liver microsomes.
abstract: Amiodarone has been shown in-vitro to inhibit the activity of cytochrome P4502D6 (CYP2D6) in nonhuman primates. However, the influence of its major metabolite, desethylamiodarone, on this isozyme activity has not been studied. To determine the effect of these drugs on dextromethorphan O-demethylation, we carried out studies in 10 human and 10 rat liver microsomal preparations. In human microsomal studies, amiodarone and the metabolite competitively inhibited dextromethorphan metabolism with mean Ki values of 52.70 +/- 5.27 and 34.40 +/- 3.30 microM, respectively. Similar studies in rat microsomes showed a competitive inhibitory effect of amiodarone and its metabolite on dextromethorphan metabolism. These data suggest that amiodarone and desethylamiodarone have an inhibitory effect on CYP2D6 in man and CYP2D1 in rats. However, it cannot be concluded that both of them are substrates of this isozyme activity.
authors.affiliation: Department of Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand.
authors.forename: S
authors.initials: S
authors.lastname: Jaruratanasirikul
authors.forename: R
authors.initials: R
authors.lastname: Hortiwakul
mesh_terms: D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003640:Dealkylation; D003864:Depression, Chemical; D003915:Dextromethorphan / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; C036116:desethylamiodarone; D000638:Amiodarone