Indinavir Increases Midazolam N-Glucuronidation in Humans: Identification of an Alternate CYP3A Inhibitor Using an In
Dan-Dan Tian1, Cathrine Leonowens1, Emily J Cox1
1Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (D.-D.T., E.J.C., V.G.-P., M.F.P.); Division of Gastroenterology and Hepatology, School of Medicine (Y.V.S.) and Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy (C.L.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Boehringer-Ingelheim Pharmaceuticals, Ridgefield, Connecticut (K.S.F., M.B.F.).
Summary
Indinavir inhibits midazolam 1'-hydroxylation, a key metabolic pathway, and may increase N-glucuronidation. This suggests indinavir could alter xenobiotic-midazolam interaction assessments.
Area of Science:
- Pharmacology
- Drug Metabolism
- Biochemistry
Background:
- Midazolam is a standard index substrate for evaluating CYP3A activity.
- Ketoconazole previously showed a shift in midazolam metabolism from 1 ahydroxylation to N-glucuronidation.
- Ketoconazole is no longer recommended as a clinical CYP3A inhibitor.
Purpose of the Study:
- To evaluate indinavir as an alternative CYP3A inhibitor.
- To characterize the effects of indinavir on midazolam 1 ahydroxylation and N-glucuronidation.
- To assess the contribution of the N-glucuronidation pathway to midazolam metabolism.
Main Methods:
- In vitro studies using recombinant CYP3A4, human liver microsomes, and cryopreserved human hepatocytes.
- In vivo studies in human volunteers (n=8).
- Analysis of midazolam and its metabolites (1 ahydroxymidazolam and N-glucuronide) in plasma and urine.
Main Results:
- Indinavir (10 μM) inhibited midazolam 1 ahydroxylation by ≥70% in vitro.
- Midazolam N-glucuronidation increased up to 2.5-fold in hepatocytes with indinavir.
- In vivo, indinavir decreased the 1 ahydroxymidazolam/midazolam AUC ratio by 80% and increased the N-glucuronide/midazolam AUC ratio by 40%.
Conclusions:
- Indinavir effectively inhibits midazolam 1 ahydroxylation, consistent with its role as a CYP3A inhibitor.
- A potential shift towards midazolam N-glucuronidation was observed in the presence of indinavir.
- Further studies are needed to determine if N-glucuronidation significantly impacts xenobiotic-midazolam interaction assessments.
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