IDENTIFICATION OF CYTOCHROME-P450 3A1 2 AS THE MAJOR P450 ISOFORM RESPONSIBLE FOR THE METABOLISM OF FENTANYL BY RAT-LIVER MICROSOMES/

The metabolism of fentanyl was investigated using rat liver microsomes to determine whether fentanyl is metabolized by rat liver microsomal cytochrome P450 and, if so, which isoform is responsible for the metab olism. Microsomes isolated from rats pretreated with phenobarbital wer e more active in metabolizing fentanyl than were microsomes from salin e controls. The major metabolic pathway of fentanyl was an oxidative N -dealkylation to norfentanyl, which was detected by a gas chromatograp h-mass selective detector (GC-MSD) method. The apparent V-m values for microsomes isolated from saline- and phenobarbital-treated rats were 2 and 9 nmol norfentanyl . min(-1) . mg(-1) microsomal protein, and th e apparent K-m values were 32 and 47 mu M, respectively. Fentanyl meta bolism was inhibited by antibodies specific for CYP3A1/2, as well as b y chemical inhibitors specific for CYP3A. These results indicate that CYP3A1/2 plays a major role in the oxidation of fentanyl to norfentany l by rat liver microsomes.