TY - JOUR T1 - Evidence for CYP3A-mediated N-deethylation of amiodarone in human liver microsomal fractions. JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 978 LP - 985 VL - 21 IS - 6 AU - G Fabre AU - B Julian AU - B Saint-Aubert AU - H Joyeux AU - Y Berger Y1 - 1993/11/01 UR - http://dmd.aspetjournals.org/content/21/6/978.abstract N2 - 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. ER -