Hans-Jürgen Seyfarth1, Nadine Favreau2, Carsten Tennert3, Claudia Ruffert2, Michael Halank4, Hubert Wirtz1, Joachim Mössner2, Jonas Rosendahl2, Peter Kovacs5, Henning Wittenburg6. 1. Division of Respiratory Medicine, Department of Internal Medicine, Neurology and Dermatology, University Hospital of Leipzig, Germany. 2. Division of Gastroenterology and Rheumatology, Department of Internal Medicine, Neurology and Dermatology, University Hospital of Leipzig, Germany. 3. Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Internal Medicine, Neurology and Dermatology, University Hospital of Leipzig, Germany. 4. Internal Medicine I Carl Gustav Carus University Dresden, Germany. 5. Integrated Research and Treatment Center Adiposity Diseases, University of Leipzig, Germany. 6. Division of Gastroenterology and Rheumatology, Department of Internal Medicine, Neurology and Dermatology, University Hospital of Leipzig, Germany; HELIOS Hospital Schleswig, Germany.
Abstract
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.
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.
Authors: Mariangela Lattanzio; Marco Ferrari; Stefano Martini; Francesca Ceriani; Andrea Imporzani; Franca Marino; Roberto De Ponti; Marco Cosentino Journal: J Med Case Rep Date: 2022-10-18