Abstract
Bedaquiline is a recently approved drug for the treatment of multidrug-resistant tuberculosis. Adverse cardiac and hepatic drug reactions to bedaquiline have been noted in clinical practice. The current study investigated bedaquiline metabolism in human hepatocytes using a metabolomic approach. Bedaquiline N-demethylation via CYP3A4 was confirmed as the major pathway in bedaquiline metabolism. In addition to CYP3A4, we found that both CYP2C8 and CYP2C19 contributed to bedaquiline N-demethylation. The Km values of CYP2C8, CYP2C19, and CYP3A4 in bedaquiline N-demethylation were 13.1, 21.3, and 8.5 µM, respectively. We also identified a novel metabolic pathway of bedaquiline that produced an aldehyde intermediate. In summary, this study extended our knowledge of bedaquiline metabolism, which can be applied to predict and prevent drug–drug interactions and adverse drug reactions associated with bedaquiline.
Footnotes
- Received November 15, 2013.
- Accepted February 10, 2014.
This research was supported in part by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK090305]; and the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant R56-AI095425].
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- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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