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Midazolam is a widely used index substrate for assessing effects of xenobiotics on CYP3A activity. A previous study involving human hepatocytes showed the primary route of midazolam metabolism, 1'-hydroxylation, shifted to N -glucuronidation in the presence of the CYP3A inhibitor ketoconazole, which may lead to an overprediction of the magnitude of a xenobiotic-midazolam interaction. Because ketoconazole is no longer recommended as a clinical CYP3A inhibitor, indinavir was selected as an alternate CYP3A inhibitor to evaluate the contribution of the N -glucuronidation pathway to midazolam metabolism. The effects of indinavir on midazolam 1'-hydroxylation and N -glucuronidation were first characterized in human-derived in vitro systems. Compared with vehicle, indinavir (10 μ M) inhibited midazolam 1'-hydroxylation by recombinant CYP3A4, human liver microsomes, and high-CYP3A activity cryopreserved human hepatocytes by ≥70%; the IC 50 obtained with hepatocytes (2.7 μ M) was within reported human unbound indinavir C max (≤5 μ M). Midazolam N -glucuronidation in hepatocytes increased in the presence of indinavir in both a concentration-dependent (1-33 μ M) and time-dependent (0-4 hours) manner (by up to 2.5-fold), prompting assessment in human volunteers ( n = 8). As predicted by these in vitro data, indinavir was a strong inhibitor of the 1'-hydroxylation pathway, decreasing the 1'-hydroxymidazolam/midazolam area under the plasma concentration versus time curve (AUC) 0-12h ratio by 80%. Although not statistically significant, the midazolam N -glucuronide/midazolam AUC 0-12h ratio increased by 40%, suggesting a shift to the N -glucuronidation pathway. The amount of midazolam N -glucuronide recovered in urine increased 4-fold but remained &lt;10% of the oral midazolam dose (2.5 mg). A powered clinical study would clarify whether N -glucuronidation should be considered when assessing the magnitude of a xenobiotic-midazolam interaction.

Indinavir Increases Midazolam N-Glucuronidation in Humans: Identification of an Alternate CYP3A Inhibitor Using an In Vitro to In Vivo Approach