T. Tateishi et al., IDENTIFICATION OF HUMAN LIVER CYTOCHROME-P-450 3A4 AS THE ENZYME RESPONSIBLE FOR FENTANYL AND SUFENTANIL N-DEALKYLATION, Anesthesia and analgesia, 82(1), 1996, pp. 167-172
Alfentanil, sufentanil, and fentanyl are synthetic opioids that are me
tabolized 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 ide
ntify the P-450 enzymes responsible for sufentanil and fentanyl metabo
lism in human liver microsomes. Microsomal preparations fortified with
a reduced nicotinamide-adenine dinucleotide phosphate-generating syst
em were incubated with 0.25 mu M H-3-fentanyl or H-3-sufentanil. Rates
of N-dealkylated metabolite formation signifi cantly correlated with
nifedipine oxidation activity (a marker of CYP3A4 activity) for fentan
yl and sufentanil (r = 0.93 and 0.87, n = 18, respectively), but not w
ith the oxidation activity for ethoxyresorufin (CYP1A2), S-mephenytoin
(CYP2C19), bufuralol (CYP2D6), or chlorzoxazone (CYP2E1). Gestodene a
nd troleandomycin (chemical inhibitors of CYP3A4) and antibody to CYP3
A4 inhibited N-dealkylation of fentanyl and sufentanil. Chemical inhib
itors of CYP2C, 2E1, and 2D6 did not inhibit N-dealkylation of fentany
l and sufentanil. Recombinant CYP3A4 expressed in Escherichia coli sho
wed N-dealkylation activity of fentanyl and sufentanil, while expresse
d CYP1A2 2C10, and 2E1 enzymes did not. We conclude that CYP3A4 is res
ponsible for fentanyl and sufentanil N-dealkylation in vitro.