title: Fentanyl inhibits metabolism of midazolam: competitive inhibition of CYP3A4 in vitro.
abstract: Fentanyl decreases clearance of midazolam administered i.v., but the mechanism remains unclear. To elucidate this mechanism, we have investigated the effect of fentanyl on metabolism of midazolam using human hepatic microsomes and recombinant cytochrome P450 isoforms (n = 6). Midazolam was metabolized to l'-hydroxymidazolam (l'-OH MDZ) by human hepatic microsomes, with a Michaelis-Menten constant (K(m)) of 5.0 (SD 2.7) mumol litre-1. Fentanyl competitively inhibited metabolism of midazolam in human hepatic microsomes, with an inhibition constant (Ki) of 26.8 (12.4) mumol litre-1. Of the seven representative human hepatic P450 isoforms, CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4, only CYP3A4 catalysed hydroxylation of midazolam, with a K(m) of 3.6 (0.8) mumol liter-1. Fentanyl competitively inhibited metabolism of midazolam to l'-OH MDZ by CYP3A4, with a Ki of 24.2 (6.8) mumol litre-1, comparable with the Ki obtained in human hepatic microsomes. These findings indicate that fentanyl competitively inhibits metabolism of midazolam by CYP3A4.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Osaka City University Medical School, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Oda
authors.forename: K
authors.initials: K
authors.lastname: Mizutani
authors.forename: I
authors.initials: I
authors.lastname: Hase
authors.forename: T
authors.initials: T
authors.lastname: Nakamoto
authors.forename: N
authors.initials: N
authors.lastname: Hamaoka
authors.forename: A
authors.initials: A
authors.lastname: Asada
mesh_terms: D018686:Anesthetics, Intravenous / Q000378:metabolism*; D001667:Binding, Competitive; D046508:Culture Techniques; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005283:Fentanyl / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D008874:Midazolam / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D018686:Anesthetics, Intravenous; D007527:Isoenzymes; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D005283:Fentanyl