Biological Activity

• DescriptionEndothelin-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_A) and B (ET_B). Ambrisentan is a diphenyl propionic acid that acts as a potent ET_A antagonist. The affinity of ambrisentan for human ET_A expressed in CHO cells is 1 nM, and the K_i value of ambrisentan for ET_A in intact cells expressing human recombinant ET_A 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 [¹²⁵I]ET-1 binding in rat bladder. Nonlinear least-squares regression analysis showed two populations of [¹²⁵I]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_d value for specific [¹²⁵I]ET-1 binding in rat bladder 2.32 times compared to that in control group, whereas the effect on the B_max value was moderate.
• MechanismAmbrisentan is a propionic acid-based selective antagonist for ET_A that can be orally administrated to treat pulmonary arterial hypertension.

• Animal Study
  Dose	Rat: 0.1 mg/kg[3] (i.p.); 0.2 mg/kg[4] (p.o.) Danio rerio: 2.5 mg/kg - 5 mg/kg[5] (i.p.)
  Administration	i.p.
  Pharmacokinetics	Animal Rats[6] Dogs[6] Dose 30 mg/kg (p.o.) 9.8 mg/kg (i.v.) 30 mg/kg (p.o.) 9.8 mg/kg (i.v.) Administration p.o. i.v. p.o. i.v. F 85.0% (p.o.) 71.5% (p.o.) T1/2 5.7 h (p.o.) 4.7 h (i.v.) 7.9 h (p.o.) 8.8 h (i.v.) Cmax 32.4 μg/ml (p.o.) 106.3 μg/ml (i.v.) 43.6 μg/ml (p.o.) 104.5 μg/ml (i.v.) AUC 161.1 μg·h/ml (p.o.) 61.9 μg·h/ml (i.v.) 115.6 μg·h/ml (p.o.) 55.4 μg·h/ml (i.v.) Tmax 1 h (p.o.) 0.03 h (i.v.) 0.5 - 2 h (p.o.) 0.033 h (i.v.) Vss 0.37 L/kg (i.v.) 0.91 L/kg (i.v.) CL 2.6 ml/min/kg (i.v.) 3.0 ml/min/kg (i.v.)

• Clinical Study

• NCT Number	Condition or disease	Phase	Recruitment Status	Estimated Study Completion Date	Locations
  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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