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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antitubercular Agents / metabolism*
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Antitubercular Agents / pharmacokinetics
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Aryl Hydrocarbon Hydroxylases / genetics
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Aryl Hydrocarbon Hydroxylases / metabolism*
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Cells, Cultured
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Cytochrome P-450 CYP2C19 / genetics
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Cytochrome P-450 CYP2C19 / metabolism*
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Cytochrome P-450 CYP2C8 / genetics
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Cytochrome P-450 CYP2C8 / metabolism*
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Cytochrome P-450 CYP3A / genetics
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Cytochrome P-450 CYP3A / metabolism*
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Dealkylation
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Diarylquinolines / metabolism*
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Diarylquinolines / pharmacokinetics
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Hepatocytes / drug effects
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Hepatocytes / enzymology
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Hepatocytes / metabolism*
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Humans
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Metabolomics
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Methylation
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Microsomes, Liver / drug effects
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Microsomes, Liver / enzymology
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Microsomes, Liver / metabolism
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Tuberculosis, Multidrug-Resistant / drug therapy
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Tuberculosis, Multidrug-Resistant / enzymology
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Tuberculosis, Multidrug-Resistant / metabolism
Substances
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Antitubercular Agents
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Diarylquinolines
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bedaquiline
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Aryl Hydrocarbon Hydroxylases
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CYP2C19 protein, human
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CYP2C8 protein, human
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Cytochrome P-450 CYP2C19
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Cytochrome P-450 CYP2C8
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human