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Association of CYP2C9 *2 With Bosentan‐Induced Liver Injury
Author(s) -
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 WC,
Witte J S,
Schwartz J B,
Kroetz D L
Publication year - 2013
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2013.143
Subject(s) - bosentan , cyp2c9 , medicine , pharmacology , liver injury , endothelin receptor antagonist , odds ratio , pharmacogenetics , pharmacokinetics , pharmacodynamics , gastroenterology , endothelin receptor , biology , receptor , genotype , cytochrome p450 , metabolism , genetics , gene
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. Clinical Pharmacology & Therapeutics (2013); 94 6, 678–686. doi: 10.1038/clpt.2013.143