Association of CYP2C9*2 With Bosentan-Induced Liver Injury
Copyright policy )Association of CYP2C9*2 With Bosentan-Induced Liver Injury
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.
- University of Washington United States
- University of Mary United States
- University of California, San Francisco United States
- GENENTECH INC United States
Endothelin Receptor Antagonists, Genetic Markers, Male, Hypertension, Pulmonary, Chronic Liver Disease and Cirrhosis, 610, Organic Anion Transporters, Polymorphism, Single Nucleotide, 618, Rare Diseases, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Humans, Pharmacology & Pharmacy, Aspartate Aminotransferases, Polymorphism, Genetic Association Studies, Cytochrome P-450 CYP2C9, Sulfonamides, Biomedical and Clinical Sciences, Liver-Specific Organic Anion Transporter 1, Liver Disease, Alanine Transaminase, Bosentan, Pharmacology and Pharmaceutical Sciences, Pulmonary, Single Nucleotide, Middle Aged, Multidrug Resistance-Associated Protein 2, Pharmacology and pharmaceutical sciences, HEK293 Cells, Hypertension, Female, Aryl Hydrocarbon Hydroxylases, Chemical and Drug Induced Liver Injury, Digestive Diseases
Endothelin Receptor Antagonists, Genetic Markers, Male, Hypertension, Pulmonary, Chronic Liver Disease and Cirrhosis, 610, Organic Anion Transporters, Polymorphism, Single Nucleotide, 618, Rare Diseases, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Humans, Pharmacology & Pharmacy, Aspartate Aminotransferases, Polymorphism, Genetic Association Studies, Cytochrome P-450 CYP2C9, Sulfonamides, Biomedical and Clinical Sciences, Liver-Specific Organic Anion Transporter 1, Liver Disease, Alanine Transaminase, Bosentan, Pharmacology and Pharmaceutical Sciences, Pulmonary, Single Nucleotide, Middle Aged, Multidrug Resistance-Associated Protein 2, Pharmacology and pharmaceutical sciences, HEK293 Cells, Hypertension, Female, Aryl Hydrocarbon Hydroxylases, Chemical and Drug Induced Liver Injury, Digestive Diseases
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