TY - JOUR T1 - Bedaquiline Metabolism: Enzymes and Novel Metabolites JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 863 LP - 866 DO - 10.1124/dmd.113.056119 VL - 42 IS - 5 AU - Ke Liu AU - Feng Li AU - Jie Lu AU - Shinlan Liu AU - Kenneth Dorko AU - Wen Xie AU - Xiaochao Ma Y1 - 2014/05/01 UR - http://dmd.aspetjournals.org/content/42/5/863.abstract N2 - 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. ER -