Identification of Human Liver Cytochrome P-450 3A4 as the Enzyme Responsible for Fentanyl and Sufentanil N-Dealkylation

Abstract

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.

Use of Fentanyl in Adolescents with Clinically Severe Obesity Undergoing Bariatric Surgery: A Pilot Study

“…It has been claimed that fentanyl is mainly metabolized to norfentanyl by CYP3A [1]. Fentanyl, however, is a high extraction-ratio drug whose metabolism is rather dependent on hepatic blood flow than on enzymatic capacity [3].…”

“…It has a rapid onset and short duration of action. Fentanyl is mainly metabolized by cytochrome P450 3A (CYP3A) to norfentanyl [1] and shows dose-independent pharmacokinetics [2]. Fentanyl has been described as a high-extraction ratio drug and its elimination is dependent on hepatic blood flow [3].…”

Pharmacokinetics, Tolerability, and Performance of a Novel Matrix Transdermal Delivery System of Fentanyl Relative to the Commercially Available Reservoir Formulation in Healthy Subjects

“…The mean area under the curve (AUCτ) and peak concentrations (C max ) of the matrix formulation were 84 838 pg⋅h/mL and 1680 pg/mL, respectively. 5 Serum fentanyl concentration increases gradually after initial patch application, generally leveling off by 24 hours and remaining relatively constant, with some fluctuation for the remainder of the 72-hour application period. Adherence of the matrix formulation was higher than the reservoir formulation (62.5 vs 56.2%, F entanyl is a synthetic opioid agent with short-acting analgesic activity.…”

Dose Proportionality of Fentanyl Buccal Tablet in Healthy Japanese Volunteers

“…Naltrexone hydrochloride was also given 12 hours after FBT administration for the treatment phases with FBT 400 µg and 800 µg. Coadministration of naltrexone with fentanyl would not be expected to affect the pharmacokinetics of fentanyl because fentanyl is a substrate of CYP3A4 [4], and naltrexone is not an inhibitor or inducer of CYP3A4 [5]. …”