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)-glucuronyltransfera se. Herein we report investigation of the effect of azoles on the enzyme-ki netics of glucuronidation of lorazepam using rabbit liver microsomes in vit ro. The K-m and V-max for LZP glucuronidation were determined to be 0.26+/- 0.08 mM and 1.25+/-0.21 nmol/min/mg protein, respectively, when evaluated i n the presence of a detergent 3-[(3-cholamidopropyl)-dimethylammonio]-1-pro panesulfonate (CHAPS) (0.8 mg/mg protein). Azoles fluconazole, miconazole, and ketoconazole competitively inhibited the glucuronidation of LZP, with K -i values of 7.17+/-4.78 mM, 0.17+/-0.08 mM, and 0.092+/-0.026 mM, respecti vely. These results are comparable to the previously reported K-i values of azoles with zidovudine (AZT) glucuronidation (1.4, 0.18, and 0.08 mM for f luconazole, miconazole, and ketoconazole, respectively) [Sampol et al., Br. J. Clin. Pharmacol., 40, 83-86, 1995]. Therefore, in order to avoid possib le side effects of LZP, the concomitant administration of LZP and azoles sh ould be carefully evaluated.