PT  - JOURNAL ARTICLE
AU  - Ke Liu
AU  - Feng Li
AU  - Jie Lu
AU  - Shinlan Liu
AU  - Kenneth Dorko
AU  - Wen Xie
AU  - Xiaochao Ma
TI  - Bedaquiline Metabolism: Enzymes and Novel Metabolites
AID  - 10.1124/dmd.113.056119
DP  - 2014 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.113.056119
4099  - http://dmd.aspetjournals.org/content/early/2014/02/10/dmd.113.056119.short
4100  - http://dmd.aspetjournals.org/content/early/2014/02/10/dmd.113.056119.full
AB  - 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.