title: Identification of the pharmacogenetic determinants of alfentanil metabolism: cytochrome P-450 3A4. An explanation of the variable elimination clearance.
abstract: There is considerable variability in the elimination clearance of the opioid analgesic alfentanil. It has been shown previously that alfentanil clearance is independent of the polymorphic debrisoquine hydroxylase (P-450 2D6), and it is therefore of interest to identify the human cytochrome P-450 enzymes involved in noralfentanil formation, the primary reaction involved in the oxidative N-dealkylation at the piperidine nitrogen. Purified human P-450 3A4 showed appreciable catalytic activity, and yeast recombinant P-450 3A4 also showed alfentanil oxidation activity. When microsomes prepared from different human liver samples were compared, noralfentanil formation activity was well correlated (r = 0.95,P less than 0.005) with nifedipine oxidation (a P-450 3A4 marker) but not with markers of other P-450s, including phenacetin O-deethylation (P-450 1A2), chlorzoxazone 6-hydroxylation (P-450 2E1), and (S)-mephenytoin 4'-hydroxylation (a P-450 2C enzyme). Using antibodies that recognize specific human P-450 enzymes (immunoinhibition techniques), it was possible to demonstrate that anti-P-450 3A4 nearly completely inhibited alfentanil oxidation activity in the human liver microsomes, but no other antibodies showed a measurable inhibitory effect. Selective chemical inhibitors of P-450 3A4, gestodene and troleandomycin, inhibited as much as 90% of the microsomal noralfentanil formation activity, but other chemical inhibitors did not show a detectable inhibitory effect. 7,8-Benzoflavone inhibited as much as 90% of the alfentanil oxidation activity of the microsomal or reconstituted P-450 3A4 system. This work indicates that P-450 3A4 contributes significantly to human liver microsomal alfentanil oxidation, whereas P-450 2D6 does not contribute.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2125.
authors.forename: C H
authors.initials: CH
authors.lastname: Yun
authors.forename: M
authors.initials: M
authors.lastname: Wood
authors.forename: A J
authors.initials: AJ
authors.lastname: Wood
authors.forename: F P
authors.initials: FP
authors.lastname: Guengerich
mesh_terms: D015760:Alfentanil / Q000378:metabolism / Q000493:pharmacokinetics; D001571:Benzoflavones / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D005283:Fentanyl / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*
chemical_list: D001571:Benzoflavones; D015760:Alfentanil; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; C047303:noralfentanil; D005283:Fentanyl