RESUMEN

BACKGROUND: Hepatotoxicity is a major side effect of treatment with bosentan in patients with pulmonary hypertension (PH). Bosentan is metabolized by the cytochrome CYP2C9 and inhibits the bile salt export pump, which is encoded by ABCB11. This suggests that genetic variants of CYP2C9 and/or ABCB11 may predispose patients to bosentan-induced liver injury. MATERIAL AND METHODS: PH patients with (n = 23) or without (n = 25) an increase of alanine aminotransferase (ALT) or aspartate-aminotransferase (AST) during bosentan therapy were included in our analysis. Functionally relevant alleles of CYP2C9 and 16 representative variants of ABCB11 were genotyped. Data were analyzed using logistic regression. RESULTS: Variants of ABCB11 were not associated with bosentan-induced liver injury. In contrast, variant alleles of CYP2C9 were more common in patients with elevated transaminases (allele frequency 52%) compared to controls (allele frequency 24%, P = 0.04, odds ratio 3.5, 95% confidence interval 1.01-11.8). CONCLUSION: Our data indicate hepatotoxicity of bosentan from decreased hepatic metabolism due to common variants of CYP2C9.

Asunto(s)

Transportadoras de Casetes de Unión a ATP/genética , Antihipertensivos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Citocromo P-450 CYP2C9/genética , Hipertensión Pulmonar/tratamiento farmacológico , Sulfonamidas/efectos adversos , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP , Adulto , Anciano , Anciano de 80 o más Años , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Bosentán , Estudios de Casos y Controles , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad