title: Inhibitory effect of azole antifungal agents on the glucuronidation of lorazepam using rabbit liver microsomes in vitro.
abstract: Azole antifungal agents (azoles) have inhibitory effects on the cytochrome P450. However, the effect of azoles on conjugative metabolism has not been given much attention. Lorazepam (LZP), a benzodiazepine sedative agent, is known to be metabolized by uridine 5'-diphosphate (UDP)-glucuronyltransferase. Herein we report investigation of the effect of azoles on the enzyme-kinetics of glucuronidation of lorazepam using rabbit liver microsomes in vitro. The Km and Vmax for LZP glucuronidation were determined to be 0.26+/-0.08 mM and 1.25+/-0.21 nmol/min/mg protein, respectively, when evaluated in the presence of a detergent 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS) (0.8 mg/mg protein). Azoles fluconazole, miconazole, and ketoconazole competitively inhibited the glucuronidation of LZP, with Ki values of 7.17+/-4.78 mM, 0.17+/-0.08 mM, and 0.092+/-0.026 mM, respectively. These results are comparable to the previously reported Ki values of azoles with zidovudine (AZT) glucuronidation (1.4, 0.18, and 0.08 mM for fluconazole, miconazole, and ketoconazole, respectively) [Sampol et al., Br. J. Clin. Pharmacol., 40, 83-86, 1995]. Therefore, in order to avoid possible side effects of LZP, the concomitant administration of LZP and azoles should be carefully evaluated.
authors.affiliation: Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Sawamura
authors.forename: H
authors.initials: H
authors.lastname: Sato
authors.forename: J
authors.initials: J
authors.lastname: Kawakami
authors.forename: T
authors.initials: T
authors.lastname: Iga
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism; D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D001667:Binding, Competitive; D003902:Detergents / Q000494:pharmacology; D015725:Fluconazole / Q000494:pharmacology; D020723:Glucuronic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D008140:Lorazepam / Q000378:metabolism*; D008297:Male; D008825:Miconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D014535:Uridine Diphosphate Glucuronic Acid / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D000935:Antifungal Agents; D001393:Azoles; D003902:Detergents; D014535:Uridine Diphosphate Glucuronic Acid; D008825:Miconazole; D020723:Glucuronic Acid; D015725:Fluconazole; D008140:Lorazepam; D007654:Ketoconazole