Inhibitory effect of azole antifungal agents on the glucuronidation of lorazepam using rabbit liver microsomes in vitro.
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.
Sawamura
R
R
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Japan.
Sato
H
H
Kawakami
J
J
Iga
T
T
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
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