Alfentanil, sufentanil, and fentanyl are synthetic opioids that are metabolized by oxidative N-dealkylation in the liver. We have previously shown that cytochrome P-450 3A4 (CYP3A4) contributes significantly to human liver microsomal alfentanil oxidation. Since identification of specific drug-metabolizing enzymes allows prediction of the variables affecting drug metabolism, the purpose of the present study was to identify the P-450 enzymes responsible for sufentanil and fentanyl metabolism in human liver microsomes. Microsomal preparations fortified with a reduced nicotinamide-adenine dinucleotide phosphate-generating system were incubated with 0.25 microM 3H-fentanyl or 3H-sufentanil. Rates of N-dealkylated metabolite formation significantly correlated with nifedipine oxidation activity (a marker of CYP3A4 activity) for fentanyl and sufentanil (r = 0.93 and 0.87, n = 18, respectively), but not with the oxidation activity for ethoxyresorufin (CYP1A2), S-mephenytoin (CYP2C19), bufuralol (CYP2D6), or chlorzoxazone (CYP2E1). Gestodene and troleandomycin (chemical inhibitors of CYP3A4) and antibody to CYP3A4 inhibited N-dealkylation of fentanyl and sufentanil. Chemical inhibitors of CYP2C, 2E1, and 2D6 did not inhibit N-dealkylation of fentanyl and sufentanil. Recombinant CYP3A4 expressed in Escherichia coli showed N-dealkylation activity of fentanyl and sufentanil, while expressed CYP1A2, 2C10, and 2E1 enzymes did not. We conclude that CYP3A4 is responsible for fentanyl and sufentanil N-dealkylation in vitro.
Because there is considerable interindividual variation in both microsomal CYP3A4 activity and CYP3A4 substrate disposition, an established probe of in vivo CYP3A4 activity would represent an important advance in clinical practice. In a previous study, no correlation was found between the "Cerythromycin breath test and urinary dapsone recovery ratio. However these drugs were administered by different routes, with the orally administered dapsone being exposed to presystemic metabolism by the gut and renal metabolism before the measurement of the urinary ratio. To overcome the variable of route of administration, the aim of this study was to determine whether the elimination of two intravenously administered CYP3A4 substrates (alfentanil and erythromycin) correlate. We compared the metabolism of alfentanil to its CYP3A4-dependent metabolite, noralfentanil, with the erythromycin breath test in 14 young healthy white men. No significant correlation was found between alfentanil metabolism and the erythromycin breath test: alfentanil clearance versus erythromycin breath test, r = 0.45, p = 0.1; partial metabolic clearance to noralfentanil versus erythromycin breath test, r = 0.35, p = 0.23.Because these two CYP3A4 substrates were administered by the same (intravenous) route, we conclude that differences in the route of administration do not explain the lack of correlation between the erythromycin breath test and other probes of CYP3A4 metabolism.The cytochrome P450 super family of heme proteins plays a central role in the metabolism of both xenobiotics and endogenous compounds) Of the four major subfamilies involved in human metabolism, cytochrome P4503A (CYP3A) may be the most important because it is responsible for the metabolism of such a large number of substrates. The spectrum of
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