Indinavir Increases Midazolam N-Glucuronidation in Humans: Identification of an Alternate CYP3A Inhibitor Using an In Vitro to In Vivo Approach.
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Tian DD, Leonowens C, Cox EJ, Gonzalez-Perez V, Frederick KS, Scarlett YV, Fisher MB, Paine MF
Indinavir Increases Midazolam N-Glucuronidation in Humans: Identification of an Alternate CYP3A Inhibitor Using an In Vitro to In Vivo Approach.
Drug Metab Dispos. 2019 Jul;47(7):724-731. doi: 10.1124/dmd.119.087007. Epub 2019 Apr 26.
- PubMed ID
- 31028057 [ View in PubMed]
- Abstract
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 muM) inhibited midazolam 1'-hydroxylation by recombinant CYP3A4, human liver microsomes, and high-CYP3A activity cryopreserved human hepatocytes by >/=70%; the IC50 obtained with hepatocytes (2.7 muM) was within reported human unbound indinavir Cmax (
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Midazolam UDP-glucuronosyltransferase 2B4 Protein Humans NoSubstrateDetails Midazolam UDP-glucuronosyltransferase 2B7 Protein Humans NoSubstrateDetails Telotristat ethyl UDP-glucuronosyltransferase 2B4 Protein Humans NoInducerDetails Telotristat ethyl UDP-glucuronosyltransferase 2B7 Protein Humans NoInducerDetails - Drug Reactions
Reaction Details Details Details
