RT Journal Article
SR Electronic
T1 Evidence for CYP3A-mediated N-deethylation of amiodarone in human liver microsomal fractions.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 978
OP 985
VO 21
IS 6
A1 G Fabre
A1 B Julian
A1 B Saint-Aubert
A1 H Joyeux
A1 Y Berger
YR 1993
UL http://dmd.aspetjournals.org/content/21/6/978.abstract
AB 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.