Influence of Mild Liver Impairment on the Pharmacokinetics and Metabolism of Bosentan, a Dual Endothelin Receptor Antagonist

Giersbergen, Paul L. M. van; Popescu, G; Bodin, F.; Dingemanse, Jasper

doi:10.1177/0091270002239701

Cited by 33 publications

(22 citation statements)

References 28 publications

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“…Bosentan is an orally available dual ET (ET A and ET B ) receptor antagonist that may cause a transient increase in hepatic enzyme levels (observed in 14% of patients in two randomised trials) [249][250][251]. Severe cases of acute hepatitis (one fatality) have been described with sitaxsentan, an ET A -receptor-selective antagonist [250].…”

Section: Managementmentioning

confidence: 99%

Pulmonary-Hepatic vascular Disorders (PHD)

Rodríguez-Roisín

Krowka

Hervé

et al. 2004

European Respiratory Journal

706

600

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Section: Managementmentioning

confidence: 99%

Pulmonary-Hepatic vascular Disorders (PHD)

Rodríguez-Roisín

Krowka

Hervé

et al. 2004

European Respiratory Journal

706

600

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“…3,4) However, bosentan is contraindicated in patients with liver cirrhosis, because of its liver toxicity. 11) In this case, bosentan produced a marked reduction in the patient's PAP, improved his ability to tolerate exercise, and prevented syncope. Additionally, the patient's liver damage was improved, perhaps because the reduction in PAP reversed hepatic congestion.…”

Section: Discussionmentioning

confidence: 68%

Efficacy and Safety of Bosentan Treatment for Portopulmonary Hypertension Associated With Syncope

et al. 2011

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SummaryPulmonary arterial hypertension (PAH) in patients with portal hypertension is also referred to as portopulmonary hypertension (PPHTN). Here, we report a case of PPHTN caused by alcoholic liver cirrhosis in a 43-year-old male who experienced repetitive syncope on exertion. The continuous monitoring of pulmonary artery pressure and radial artery pressure revealed that his PAH was aggravated with a drop in systemic arterial pressure during an exercise test. Bosentan, an endothelin A/B receptor antagonist, improved the patient's hemodynamic parameters and abolished his syncope without adverse effects. This is the first report that bosentan may be effective and safe for PPHTN associated with syncope. (Int Heart J 2011; 52: 243-245) Key words: Portopulmonary hypertension, Syncope, Bosentan, Liver cirrhosis P ortopulmonary hypertension (PPHTN) is defined as pulmonary arterial hypertension (PAH) associated with portal hypertension.1) The diagnostic criteria for PPHTN are abnormal increases in the mean pulmonary arterial pressure (PAP) (> 25 mmHg) and pulmonary vascular resistance (> 240 dynes/second/cm 5 ), and a normal pulmonary capillary wedge pressure (< 15 mmHg) in patients with liver disease causing clinical portal hypertension.1) The prognosis of PPHTN is very poor, 2) and the pathogenesis and management of PPHTN are not well understood.We present a patient with PPHTN associated with syncope who was treated successfully with the oral endothelin A/B receptor antagonist bosentan. Case ReportA 43-year-old male was admitted to another hospital for deterioration of alcohol-related liver damage in September 2009. He recovered after rest and abstinence from alcohol. However, he developed repetitive faintness and syncope during walking or light exertion after leaving the hospital. During an exercise treadmill test, which was performed according to the Bruce protocol, electrocardiography revealed a shift from sinus tachycardia (120 bpm) to an atrioventricular junctional rhythm (60 bpm) with sinus pauses, followed by syncope at 4 minutes in that protocol ( Figure 1A). He was admitted to our hospital for syncope in November 2009.On physical examination, his second heart sound was increased and a pansystolic murmur attributable to a tricuspid regurgitation was detected. No leg edema or cranial or peripheral neuropathy was observed. Resting electrocardiography showed a normal sinus rhythm with negative T waves in the right precordial leads. Echocardiography revealed a tricuspid regurgitation with a high pressure gradient (55 mmHg), a dilated right ventricle and a leftward bulging of the interventricular septum, especially in systole ( Figure 1B and 1C). Cardiac catheterization showed that the coronary arteries and left ventricular wall motion were normal. His pulmonary capillary wedge pressure and systemic vascular resistance were within the normal range (14 mmHg and 1493 dynes/second/cm 5 , respectively). However, his pulmonary arterial pressure (PAP) and pulmonary vascular resistance were high (68/30 [43] mmHg and ...

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“…Furthermore, the fact that bosentan plasma levels were not measured, at least in some C-P class A patients, is also a limitation of the study. The pharmacokinetics of bosentan in C-P class A patients have been studied previously [21], but these patients were not diagnosed with PoPH. Finally, plasma levels may not necessary reflect tissular drug action on the receptor.…”

Section: Discussionmentioning

confidence: 99%

“…In a small study, treatment with bosentan proved to be efficacious and well tolerated in patients with C-P class A cirrhosis [19,20]. Furthermore, the pharmacokinetics of bosentan and its metabolites in patients with C-P class A did not differ to a relevant extent from those in healthy subjects [21]. However, to date, there has been only one case report of treatment with bosentan in a single patient with more advanced liver disease [17].…”

mentioning

confidence: 99%

Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension

Savale

Magnier²,

Pavec

et al. 2012

European Respiratory Journal

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Data on treatment of patients with portopulmonary hypertension (PoPH) are limited, as they are usually excluded from randomised controlled trials with pulmonary arterial hypertension (PAH)-specific therapies. This study investigated the short-and long-term efficacy/safety of bosentan in these patients, as well as its pharmacokinetics.All 34 consecutive patients with PoPH treated with first-line bosentan (December 2002 to July 2009) were retrospectively evaluated. Assessments included the New York Heart Association functional class (NYHA FC), blood tests, haemodynamics, 6-min walk distance (6MWD) and eventfree status. The pharmacokinetics of bosentan in five patients with Child-Pugh (C-P) class B cirrhosis were compared with idiopathic PAH patients.Significant improvements from baseline were observed in NYHA FC, 6MWD and haemodynamics, and were largely maintained during follow-up. Patients with C-P class B cirrhosis (n59) had significantly larger haemodynamic improvement after mean¡SD 5¡2 months. Mean followup time was 43¡19 months; four patients died and seven patients had significant elevation of liver enzymes (annual rate 5.5%). Plasma concentrations of bosentan were higher in patients with C-P class B cirrhosis than those observed in idiopathic PAH.These data confirm the benefit of bosentan treatment for patients with PoPH. Haemodynamic improvements were particularly pronounced in patients with more severe cirrhosis. The safety profile of bosentan was consistent with previous studies.

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Influence of Mild Liver Impairment on the Pharmacokinetics and Metabolism of Bosentan, a Dual Endothelin Receptor Antagonist

Cited by 33 publications

References 28 publications

Pulmonary-Hepatic vascular Disorders (PHD)

Pulmonary-Hepatic vascular Disorders (PHD)

Efficacy and Safety of Bosentan Treatment for Portopulmonary Hypertension Associated With Syncope

Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension

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