Ambrisentan is an orally active, highly selective antagonist of endothelin receptor ETA-selective antagonist, with an IC50 value of 0.6nM[1]. Ambrisentan inhibits the OATP1B1 and OATP1B3, with IC50 values of 47.0 and 44.6µM, respectively[2]. Ambrisentan has been widely used to improve liver function and hemodynamics in rat models of nonalcoholic steatohepatitis[3].
In vitro, Ambrisentan treatment at 50µM for 4 days significantly increased the mRNA levels of ABCB1 and CYP2C9 in LS180 cells[4]. Under hypoxic conditions, 0.02nM Ambrisentan treatment for 24h markedly enhanced autophagy in high glucose-treated human pulmonary artery endothelial cells (hPAECs)[5].
In vivo, Ambrisentan treatment via oral administration at a dose of 10mg/kg/day for 2 weeks significantly inhibited liver metastasis, reduced myeloid cell accumulation, and improved survival in 4T1 breast cancer-bearing mice[6]. Intraperitoneal injection of Ambrisentan at a dose of 5mg/kg/day for one week significantly reduced portal vein injury and alleviated biliary senescence in Mdr2-/- mice[7]. Oral administration of Ambrisentan at a dose of 2.5mg/kg/day for 4 weeks attenuated the progression of liver fibrosis without affecting steatosis in a mouse model of nonalcoholic steatohepatitis[8].
References:
[1] Hou J, Liu S, Zhang X, et al. Structural basis of antagonist selectivity in endothelin receptors[J]. Cell Discovery, 2024, 10(1): 79.
[2] Lepist E I, Gillies H, Smith W, et al. Evaluation of the endothelin receptor antagonists ambrisentan, bosentan, macitentan, and sitaxsentan as hepatobiliary transporter inhibitors and substrates in sandwich-cultured human hepatocytes[J]. PloS one, 2014, 9(1): e87548.
[3] Bravo M, Raurell I, Barberá A, et al. Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH[J]. Disease models & mechanisms, 2021, 14(5): dmm048884.
[4] Weiss J, Herzog M, Haefeli W E. Differential modulation of the expression of important drug metabolising enzymes and transporters by endothelin-1 receptor antagonists ambrisentan and bosentan in vitro[J]. European journal of pharmacology, 2011, 660(2-3): 298-304.
[5] Cabiati M, Biondi F, Ghelardoni S, et al. Ambrisentan Retains Its Pro‐Autophagic Activity on Human Pulmonary Artery Endothelial Cells Exposed to Hypoxia in an In Vitro Model Mimicking Diabetes[J]. Journal of Cellular and Molecular Medicine, 2025, 29(7): e70528.
[6] Kappes L, Amer R L, Sommerlatte S, et al. Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis[J]. Scientific reports, 2020, 10(1): 15931.
[7] Owen T, Carpino G, Chen L, et al. Endothelin receptor-A inhibition decreases ductular reaction, liver fibrosis, and angiogenesis in a model of cholangitis[J]. Cellular and Molecular Gastroenterology and Hepatology, 2023, 16(4): 513-540.
[8] Okamoto T, Koda M, Miyoshi K, et al. Antifibrotic effects of ambrisentan, an endothelin-A receptor antagonist, in a non-alcoholic steatohepatitis mouse model[J]. World Journal of Hepatology, 2016, 8(22): 933.
Ambrisentan是一种口服活性、高选择性的内皮素受体ETA的选择性拮抗剂，IC50值为0.6nM[1]。Ambrisentan可抑制OATP1B1和OATP1B3，IC50值分别为47.0µM和44.6µM[2]。Ambrisentan已广泛用于改善非酒精性脂肪性肝炎大鼠模型的肝功能与血流动力学[3]。
在体外，使用50µM的Ambrisentan处理LS180细胞4天显著提高了ABCB1和CYP2C9的mRNA水平[4]。在低氧条件下，使用0.02nM的Ambrisentan处理高糖培养的人肺动脉内皮细胞（hPAECs）24小时显著增强了细胞自噬[5]。
在体内，以10mg/kg/day的剂量口服Ambrisentan，持续2周显著抑制了4T1乳腺癌荷瘤小鼠的肝转移，减少了髓系细胞积累并提高了生存率[6]。腹腔注射5mg/kg/day剂量的Ambrisentan连续一周，显著减轻了Mdr2-/-小鼠的门静脉损伤并缓解了胆道衰老[7]。以2.5mg/kg/day的剂量口服Ambrisentan，持续4周，在非酒精性脂肪性肝炎小鼠模型中减轻了肝纤维化的进展且不影响脂肪变性[5]。