Association of cyp2c9*2 with bosentan-induced liver injury

S. M. Markova, T. De Marco, N. Bendjilali, E. A. Kobashigawa, J. Mefford, J. Sodhi, H. Le, C. Zhang, J. Halladay, A. E. Rettie, C. Khojasteh, D. McGlothlin, A. H.B. Wu, W. C. Hsueh, J. S. Witte, J. B. Schwartz, D. L. Kroetz

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Abstract

Bosentan (Tracleer) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, and SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and DILI. After adjusting for body mass index, CYP2C9*2 was the only polymorphism associated with ALT, AST, and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; odds ratio 95% CI = 2.29-∞, P = 0.003, respectively). Bosentan metabolism by CYP2C9*2 in vitro was significantly reduced compared with CYP2C9*1 and was comparable to that by CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment.

Original languageEnglish (US)
Pages (from-to)678-686
Number of pages9
JournalClinical Pharmacology and Therapeutics
Volume94
Issue number6
DOIs
StatePublished - Dec 1 2013

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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    Markova, S. M., De Marco, T., Bendjilali, N., Kobashigawa, E. A., Mefford, J., Sodhi, J., Le, H., Zhang, C., Halladay, J., Rettie, A. E., Khojasteh, C., McGlothlin, D., Wu, A. H. B., Hsueh, W. C., Witte, J. S., Schwartz, J. B., & Kroetz, D. L. (2013). Association of cyp2c9*2 with bosentan-induced liver injury. Clinical Pharmacology and Therapeutics, 94(6), 678-686. https://doi.org/10.1038/clpt.2013.143