title: Hemodynamics and pharmacokinetics of tezosentan, a dual endothelin receptor antagonist, in patients with cirrhosis.
abstract: OBJECTIVE
  To assess the effect of tezosentan, a parenteral dual ET receptor antagonist, on splanchnic and systemic hemodynamics in patients with cirrhosis. In addition, the safety, pharmacokinetics, and pharmacodynamics of tezosentan were evaluated.
  
  
  METHODS
  The population consisted of patients with cirrhosis with clinically significant portal hypertension. This was a randomized, double-blind, multicenter study. The patients were randomized 3:1 to tezosentan (3 mg/h for 2-3 h) or placebo. HVPG, hepatic blood flow (HBF, ICG method), and systemic arterial pressures were measured before and after tezosentan administration. Plasma concentrations of tezosentan and ET-1 were determined peripherally and in the hepatic vein.
  
  
  RESULTS
  Eighteen patients received tezosentan and six placebo. Baseline clinical, biochemical, and hemodynamic characteristics were balanced between the two groups. There was no significant treatment effect on HVPG. The extraction ratio (0.31), the plasma clearance of ICG (280 ml/min), and the HBF (1,430 ml/min) did not show any relevant changes during the infusion of tezosentan, and there were no differences between placebo- and tezosentan-treated patients. A linear relationship was observed between the maximum-fold increase in ET-1 concentration and the steady-state tezosentan plasma concentration (r = 0.82). There was a strong correlation (r = 0.88) between plasma clearance of ICG and that of tezosentan (10.2 l/h). Arterial pressure and heart rate did not significantly change in either group.
  
  
  CONCLUSIONS
  In patients with cirrhosis, a 2- to 3-h tezosentan infusion was safe and well tolerated but did not change the HVPG. Tezosentan infusion had no influence on the extraction ratio and plasma clearance of ICG and did not change HBF.
authors.affiliation: Unité 773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, INSERM, Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Lebrec
authors.forename: Jaime
authors.initials: J
authors.lastname: Bosch
authors.forename: Rajiv
authors.initials: R
authors.lastname: Jalan
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Dudley
authors.forename: Rada
authors.initials: R
authors.lastname: Jessic
authors.forename: Richard
authors.initials: R
authors.lastname: Moreau
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Garcia-Pagan
authors.forename: Rajeshwar P
authors.initials: RP
authors.lastname: Mookerjee
authors.forename: Eleonora
authors.initials: E
authors.lastname: Chiossi
authors.forename: Paul L M
authors.initials: PL
authors.lastname: Van Giersbergen
authors.forename: Andjela
authors.initials: A
authors.lastname: Kusic-Pajic
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000959:Antihypertensive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000209:etiology; D007263:Infusions, Parenteral; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000097:blood / Q000503:physiopathology* / Q000821:virology; D008104:Liver Cirrhosis, Alcoholic / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011725:Pyridines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013152:Splanchnic Circulation / Q000187:drug effects; D013777:Tetrazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011725:Pyridines; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan
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