LIVER MICROSOMES

The microsomal metabolism of fentanyl, a synthetic opioid com-monly used in anesthesia, was investigated in human liver. Incu-bation of fentanyl with human hepatic microsomes fortified with NADPH resulted in the formation of a single major metabolite, namely norfentanyl, as determined by GC/MS. No evidence was obtained for the formation of either desproprionylfentanyl or N-phenylpropionamide, the latter arising via N-dealkylation of the fentanyl amide nitrogen. Kinetic analysis of microsomal fentanyl oxidation revealed a single Km of I 17 zM and a Vmax of 3.86 nmol of norfentanyl formed/min/nmol of cytochrome P450 (P450). Stud-ies using chemical inhibitors of human P450 enzymes revealed that only agents known to inhibit CYP3A4 (e.g. ketoconazole and eryth-romycin) were capable of strongly inhibiting (90%) microsomal fentanyl oxidation. Marked inhibition (>90%) of norfentanyl forma