METABOLISM OF FENTANYL, A SYNTHETIC OPIOID ANALGESIC, BY HUMAN LIVER-MICROSOMES - ROLE OF CYP3A4

The microsomal metabolism of fentanyl, a synthetic opioid commonly use d in anesthesia, was investigated in human liver, Incubation of fentan yl with human hepatic microsomes fortified with NADPH resulted in the formation of a single major metabolite, namely norfentanyl, as determi ned by GC/MS. No evidence was obtained for the formation of either des proprionylfentanyl or N-phenylpropionamide, the latter arising via N-d ealkylation of the fentanyl amide nitrogen. Kinetic analysis of micros omal fentanyl oxidation revealed a single K-m of 117 mu M and a V-max of 3.86 nmol of norfentanyl formed/min/nmol of cytochrome P450 (P450). Studies using chemical inhibitors of human P450 enzymes revealed that only agents known to inhibit CYP3A4 (e.g, ketoconazole and erythromyc in) were capable of strongly inhibiting (greater than or equal to 90%) microsomal fentanyl oxidation, Marked inhibition (>90%) of norfentany l formation by liver microsomes was also observed with polyclonal anti bodies to CYP3A4, whereas antibodies to other human P450s were without effect. Furthermore, rates of norfentanyl production by 10 individual human liver samples were highly correlated (r(2) = 0.876, F = 56.46, p < 0.001) with immunochemically determined levels of CYP3A4 present i n the samples but not with levers of CYP2C8, CYP2C9, CYP2C19, or CYPPE 1, Our results indicate that CYP3A4 is the major catalyst involved in fentanyl oxidation to norfentanyl in human liver, Alterations in CYP3A 4 levels or activity, as well as the concomitant administration of oth er therapeutic agents metabolized by this P450 enzyme, could lead to m arked perturbations in fentanyl disposition and, hence, analgesic resp onse.