生物活性

• 描述Endothelin-1 (ET-1) is the most predominant isoform of an isopeptides family that has potent vasoconstrictor activity. ET-1 is mediated by two receptor subtypes, endothelin receptor type A (ET<sub>A</sub>) and B (ET<sub>B</sub>). Ambrisentan is a diphenyl propionic acid that acts as a potent ET<sub>A</sub> antagonist. The affinity of ambrisentan for human ET<sub>A</sub> expressed in CHO cells is 1 nM, and the K<sub>i</sub> value of ambrisentan for ET<sub>A</sub> in intact cells expressing human recombinant ET<sub>A</sub> is 0.63 nM. In LS180 cells, the mRNA expressions of CYP3A4, CYP2C9, ABCB1, SLCO1B1, SLCO2B1, PXR were significantly induced by 50 µM ambrisentan after 4-day incubation. The same treatment also resulted in 5.1-fold induction of P-gp expression and 1.2-fold of PXR expression. Ambrisentan at the concentration from 0.1 - 20 µM had a dose-dependent effect on PXP activity in LS180 cells. In OATP1B1 over-expressing cell lines, ambrisentan inhibited intracellular 8-FcA fluorescence with an IC50 value at 27.3 ± 8.6 µM. Ambrisentan (0.1 – 100 nM) showed dose-dependent inhibition on specific [<sup>125</sup>I]ET-1 binding in rat bladder. Nonlinear least-squares regression analysis showed two populations of [<sup>125</sup>I]ET-1 binding sites for ambrisentan, one with high affinity (pIC50 = 9.4 ± 0.7 nM), and the other with low affinity (pIC50 = 7.7 ± 0.5 nM). Moreover, 6 nM ambrisentan increased the K<sub>d</sub> value for specific [<sup>125</sup>I]ET-1 binding in rat bladder 2.32 times compared to that in control group, whereas the effect on the B<sub>max</sub> value was moderate.
• 作用机制Ambrisentan is a propionic acid-based selective antagonist for ET<sub>A</sub> that can be orally administrated to treat pulmonary arterial hypertension.

• 动物研究
  剂量	Rat: 0.1 mg/kg<a href="#ulrefer"><sup>[3]</sup></a> (i.p.); 0.2 mg/kg<a href="#ulrefer"><sup>[4]</sup></a> (p.o.)<br>Danio rerio: 2.5 mg/kg - 5 mg/kg<a href="#ulrefer"><sup>[5]</sup></a> (i.p.)
  给药途径	i.p.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01467791	-	-	Unknown	January 2018	United States, Ohio ... more >> University of Cincinnati Recruiting Cincinnati, Ohio, United States, 45267 Contact: Rebecca Ingledue    513-584-6252    ingledra@ucmail.uc.edu    Principal Investigator: Robert P Baughman, MD          Sub-Investigator: Peter Engel, MD Collapse <<
  NCT01347216	-	-	Recruiting	June 2020	Belgium ... more >> Dept. of Pneumology, University Recruiting Leuven, Belgium Contact: Marion Delcroix, MD, PhD          Principal Investigator: Marion Delcroix, MD, PhD          Germany DRK-Klinikum Köpenick Recruiting Berlin, Germany Contact: Christian Opitz, MD, PhD          Principal Investigator: Christian Opitz, MD, PhD          Lung Centre, University of Giessen Recruiting Giessen, Germany Contact: Ardeschir Ghofrani, MD, PhD          Principal Investigator: Ardeschir Ghofrani, MD          Sub-Investigator: Melanie Thamm, MD          Department of Pulmology; Hannover Medical School Recruiting Hannover, Germany Contact: Marius M Hoeper          Principal Investigator: Marius M Hoeper, MD, PhD          Sub-Investigator: Karen Olsson, MD          German Heart Centre Recruiting Munich, Germany Contact: Harald Kaemmerer, MD,. PhD          Principal Investigator: Harald Kaemmerer, MD, PhD          Ireland Mater Misericordiae Recruiting Dublin, Ireland Contact: Sean Gaine, MD, PhD          Principal Investigator: Sean Gaine, MD, PhD          Italy Department of Cardiovascular and Respiratory Sciences, University La Sapienza Recruiting Rome, Italy Contact: Dario Vizza, MD, PhD          Principal Investigator: Dario Vizza, MD, PhD          Switzerland Dept. for Rheumatology, University Hospital Recruiting Zurich, Switzerland Contact: Oliver Distler, MD, PhD          Principal Investigator: Oliver Distler, MD, PhD Collapse <<
  NCT02565030	-	-	Active, not recruiting	October 2021	United Kingdom ... more >> Sheffield Teaching Hospitals NHS Foundation Trust Sheffield, South Yorkshire, United Kingdom, S10 2JF Collapse <<

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• 参考文献

• [1] Yokoyama Y, Osano A, et al. Endothelin-1 receptors in rat tissues: characterization by bosentan, ambrisentan and CI-1020. Biol Pharm Bull. 2014;37(3):461-5.

  [2] Weiss J, Herzog M, Haefeli WE. Differential modulation of the expression of important drug metabolising enzymes and transporters by endothelin-1 receptor antagonists ambrisentan and bosentan in vitro. Eur J Pharmacol. 2011 Jun 25;660(2-3):298-304.

  [3] Radiloff D, Zhao Y, et al. Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude. PLoS One. 2014 Jun 24;9(6):e99309.

  [4] Lee H, Yeom A, et al. Effect of Ambrisentan Therapy on the Expression of Endothelin Receptor, Endothelial Nitric Oxide Synthase and NADPH Oxidase 4 in Monocrotaline-induced Pulmonary Arterial Hypertension Rat Model. Korean Circ J. 2019 Sep;49(9):866-876.

  [5] Muthuraman A, Nafisa K, et al. Role of ambrisentan (selective endothelin-A receptor antagonist) on cigarette smoke exposure induced cognitive impairment in Danio rerio. Life Sci. 2019 Apr 1;222:133-139.

  [6] Ambrisentan

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