Abstract
The comorbidities of tuberculosis and diseases such as HIV require long-term treatment with multiple medications. Despite substantial in vitro and in vivo information on effects of rifampicin and isoniazid on human CYPs, there is limited published data regarding the inhibitory effects of other anti-TB drugs on human CYPs and UGTs. The inhibitory effects of five first-line anti-TB drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and rifabutin), and the newly approved bedaquiline, were evaluated for six common human hepatic UGT enzymes (UGT1A1, 1A4, 1A6, 1A9, 2B7 and 2B15) in vitro using HLMs. Pyrazinamide, ethambutol, rifabutin and bedaquiline were also studied for their inhibitory effects on eight of the most common human CYP enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A). Rifabutin inhibited multiple CYPs to varying degrees in vitro, but with all IC50 values exceeding 25 µM. Rifabutin and rifampicin also inhibited several human UGTs including UGT1A4. The Ki value for rifabutin on human hepatic UGT1A4 was 2 μM. Finally, the six anti-TB drugs produced minimal inhibition of acetaminophen glucuronidation in vitro. Overall, the findings do not raise major concerns regarding metabolic inhibition of human hepatic CYPs and UGTs by the tested anti-TB drugs.
Footnotes
- Received March 21, 2017.
- Accepted June 22, 2017.
↵1 Current affiliation: University of Florida College of Medicine, Gainesville, Florida.
This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health [Grant HD071779].
↵This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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