title: Bedaquiline metabolism: enzymes and novel metabolites.
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.
authors: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (K.L., J.L., S.L., W.X., X.M.); and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (F.L., K.D.).
authors: Ke
authors: K
authors: Liu
authors: Feng
authors: F
authors: Li
authors: Jie
authors: J
authors: Lu
authors: Shinlan
authors: S
authors: Liu
authors: Kenneth
authors: K
authors: Dorko
authors: Wen
authors: W
authors: Xie
authors: Xiaochao
authors: X
authors: Ma
mesh_terms: D000995:Antitubercular Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism*; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D003640:Dealkylation; D064687:Diarylquinolines / Q000378:metabolism* / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D055432:Metabolomics; D008745:Methylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; C493870:bedaquiline; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C450259:CYP2C8 protein, human; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human