title: Evidence for CYP3A-mediated N-deethylation of amiodarone in human liver microsomal fractions.
abstract: Metabolism of amiodarone to its N-deethylated derivative was investigated on a bank of human hepatic microsomal fractions, two of them lacking the CYP2D6 isozyme. Michaelis-Menten constants for amiodarone N-deethylation were 0.33 +/- 0.11 microM and 2.38 +/- 0.74 nmol/min/mg for KM and Vmax. The specific involvement of CYP3A gene subfamily in amiodarone N-deethylation was provided by the following observations: 1) metabolism of amiodarone is inhibited in a concentration-dependent manner by ketoconazole, a specific CYP3A inhibitor, and by nifedipine, a specific substrate for CYP3A gene subfamily, with IC50 of 0.3 and 25 microM, respectively; 2) nifedipine competitively inhibits amiodarone metabolism with a Ki of 38 microM; 3) amiodarone N-deethylation is increased following incubation with hepatic microsomal fractions prepared from CYP3A-inducers such as rifampycin and triacetyloleandomycin, but also following the in vitro disruption of the "cytochrome P-450-Fe-(II)-triacetyloleandomycin nitroso derivative" complex; 4) antibodies raised against either rabbit or baboon monkey CYP3A gene subfamily inhibit amiodarone N-deethylation; and 5) microsomal fractions that specifically express CYP3A4 biotransform amiodarone to its N-deethylated derivative. These studies indicate that CYP3A isozyme(s) mainly metabolize amiodarone to its N-deethylated derivative in human hepatic microsomal fractions.
authors.affiliation: Sanofi Recherche, Metabolism and Pharmacokinetics Department, Montpellier, France.
authors.forename: G
authors.initials: G
authors.lastname: Fabre
authors.forename: B
authors.initials: B
authors.lastname: Julian
authors.forename: B
authors.initials: B
authors.lastname: Saint-Aubert
authors.forename: H
authors.initials: H
authors.lastname: Joyeux
authors.forename: Y
authors.initials: Y
authors.lastname: Berger
mesh_terms: D000328:Adult; D000478:Alkylation; D000638:Amiodarone / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D002460:Cell Line; D002845:Chromatography; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007206:Individuality; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged; D009543:Nifedipine / Q000494:pharmacology; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011817:Rabbits; D012680:Sensitivity and Specificity
chemical_list: D000906:Antibodies; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D009543:Nifedipine; D000638:Amiodarone; D007654:Ketoconazole