Abstract
Bedaquiline is a recently approved drug for treatment of multi-drug resistant tuberculosis. Adverse cardiac and hepatic drug reactions of bedaquiline have been noted in clinical practice. The current study investigated bedaquiline metabolism in human hepatocytes using a metabolomic approach. Bedaquiline N-demethylation via cytochrome P450 3A4 (CYP3A4) was confirmed as the major pathway in bedaquiline metabolism. Besides 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.
- The American Society for Pharmacology and Experimental Therapeutics