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Association of CYP2C9*2 with Bosentan-Induced Liver Injury.


Clin Pharmacol Ther. 2013 Jul 17;


Authors: Markova SM, De Marco T, Bendjilali N, Kobashigawa EA, Mefford J, Sodhi J, Le H, Zhang C, Halladay J, Rettie AE, Khojasteh C, McGlothlin D, Wu AH, Hsueh WC, Witte JS, Schwartz JB, Kroetz DL


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, SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with ALT, AST and DILI. After adjusting for BMI, CYP2C9*2 was the only polymorphism associated with ALT, AST and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; OR 95% CI = 2.29 - ∞, P = 0.003, respectively). Bosentan metabolism in vitro by CYP2C9*2 was significantly reduced compared to CYP2C9*1 and was comparable to 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); accepted article preview online 17 July 2013 doi:10.1038/clpt.2013.143.

PMID: 23863877 [PubMed - as supplied by publisher]