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PubMed1998

The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan Hypertension Investigators.

BACKGROUND: Endothelin is a powerful vasoconstrictor peptide derived from the endothelium. We evaluated the contribution of endothelin to blood-pressure regulation in patients with essential hypertension by studying the effect of an endothelin-receptor antagonist, bosentan. METHODS: We studied 293 patients with mild-to-moderate essential hypertension. After a placebo run-in period of four to six weeks, patients were randomly assigned to receive one of four oral doses of bosentan (100, 500, or 1000 mg once daily or 1000 mg twice daily), placebo, or the angiotensin-converting-enzyme inhibitor enalapril (20 mg once daily) for four weeks. Blood pressure was measured before and after treatment. RESULTS: As compared with placebo, bosentan resulted in a significant reduction in diastolic pressure with a daily dose of 500 or 2000 mg (an absolute reduction of 5.7 mm Hg at each dose), which was similar to the reduction with enalapril (5.8 mm Hg). There were no significant changes in heart rate. Bosentan did not result in activation of the sympathetic nervous system (as determined by measurement of the plasma norepinephrine level) or the renin-angiotensin system (as determined by measurements of plasma renin activity and angiotensin II levels). CONCLUSIONS: An endothelin-receptor antagonist, bosentan, significantly lowered blood pressure in patients with essential hypertension, suggesting that endothelin may contribute to elevated blood pressure in such patients. The favorable effect of treatment with bosentan on blood pressure occurred without reflexive neurohormonal activation.

Adult↗
PubMed2004

Clinical pharmacology of bosentan, a dual endothelin receptor antagonist.

Bosentan, a dual endothelin receptor antagonist, is indicated for the treatment of patients with pulmonary arterial hypertension (PAH). Following oral administration, bosentan attains peak plasma concentrations after approximately 3 hours. The absolute bioavailability is about 50%. Food does not exert a clinically relevant effect on absorption at the recommended dose of 125 mg. Bosentan is approximately 98% bound to albumin and, during multiple-dose administration, has a volume of distribution of 30 L and a clearance of 17 L/h. The terminal half-life after oral administration is 5.4 hours and is unchanged at steady state. Steady-state concentrations are achieved within 3-5 days after multiple-dose administration, when plasma concentrations are decreased by about 50% because of a 2-fold increase in clearance, probably due to induction of metabolising enzymes. Bosentan is mainly eliminated from the body by hepatic metabolism and subsequent biliary excretion of the metabolites. Three metabolites have been identified, formed by cytochrome P450 (CYP) 2C9 and 3A4. The metabolite Ro 48-5033 may contribute 20% to the total response following administration of bosentan. The pharmacokinetics of bosentan are dose-proportional up to 600 mg (single dose) and 500 mg/day (multiple doses). The pharmacokinetics of bosentan in paediatric PAH patients are comparable to those in healthy subjects, whereas adult PAH patients show a 2-fold increased exposure. Severe renal impairment (creatinine clearance 15-30 mL/min) and mild hepatic impairment (Child-Pugh class A) do not have a clinically relevant influence on the pharmacokinetics of bosentan. No dosage adjustment in adults is required based on sex, age, ethnic origin and bodyweight. Bosentan should generally be avoided in patients with moderate or severe hepatic impairment and/or elevated liver aminotransferases. Ketoconazole approximately doubles the exposure to bosentan because of inhibition of CYP3A4. Bosentan decreases exposure to ciclosporin, glibenclamide, simvastatin (and beta-hydroxyacid simvastatin) and (R)- and (S)-warfarin by up to 50% because of induction of CYP3A4 and/or CYP2C9. Coadministration of ciclosporin and bosentan markedly increases initial bosentan trough concentrations. Concomitant treatment with glibenclamide and bosentan leads to an increase in the incidence of aminotransferase elevations. Therefore, combined use with ciclosporin and glibenclamide is contraindicated and not recommended, respectively. The possibility of reduced efficacy of CYP2C9 and 3A4 substrates should be considered when coadministered with bosentan. No clinically relevant interaction was detected with the P-glycoprotein substrate digoxin. In healthy subjects, bosentan doses >300 mg increase plasma levels of endothelin-1. The drug moderately reduces blood pressure, and its main adverse effects are headache, flushing, increased liver aminotransferases, leg oedema and anaemia. In a pharmacokinetic-pharmacodynamic study in PAH patients, the haemodynamic effects lagged the plasma concentrations of bosentan.

Antihypertensive Agents↗
PubMed1996

Bosentan-improved cardiopulmonary vascular performance and increased plasma levels of endothelin-1 in porcine endotoxin shock.

1. To evaluate the possible contribution of endothelin-1 (ET-1) to the pathophysiology of porcine septic shock, the non-peptide, mixed ET-receptor antagonist, bosentan (RO 47-0203) was administered (5 mg kg-1, i.v.) 30 min before infusion of lipopolysaccharide (LPS) (E. coli., serotype 0111:B4) (15 micrograms kg-1 h-1) and at 3.5 h of endotoxaemia in six anaesthetized and mechanically ventilated pigs. Six other pigs served as controls and received only LPS infusion. Pulmonary and systemic haemodynamics as well as splenic, renal and intestinal blood flows were measured continuously. Release and synthesis of ET-1 and Big ET-1 were also measured. 2. Only three of the six pigs in the control group survived 3 h of LPS infusion while in the bosentantreated group all six pigs were alive at that time. A biphasic increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR) was seen in control pigs. Pretreatment with bosentan did not influence the first peak but markedly attenuated the second, more prolonged increase in MPAP and PVR. The second dose of bosentan completely restored these parameters to pre-LPS levels. The LPS-induced changes in mean arterial blood pressure, heart rate and systemic vascular resistance were similar in both groups, while cardiac output (CO) was significantly higher in the bosentan-treated group. The second bosentan dose increased CO and splenic and intestinal blood flow without further lowering of blood pressure. 3. Bosentan caused an increase of the basal arterial plasma levels of ET-1-like immunoreactivity (LI), from 16.8 +/- 1.3 pM to 49.6 +/- 10.0 pM (n = 6, P < 0.01). However, the rate of the increase of ET-1 levels during the LPS infusion was not affected by bosentan. Repeated administration of bosentan during LPS infusion caused an additional increase of ET-1-LI levels. Neither the basal levels of Big ET-LI nor the LPS induced 8 fold increase in Big ET-LI were changed by bosentan. The level of preproET-1 mRNA in the lung was increased about 3 fold after 4.5 h of LPS treatment. This elevation was not influenced by bosentan. 4. From these studies using bosentan, a non-peptide, selective and mixed ET-receptor antagonist, we conclude that during LPS-induced shock bosentan can abolish the late phase pulmonary hypertension and improve cardiac output as well as increase blood flow to the splenic and intestinal vascular beds without causing a further decrease in mean arterial blood pressure. Further investigations in the clinical setting are needed to evaluate the use of ET-receptor antagonists, such as bosentan, in treatment of septic shock.

Animals↗
PubMed1999

L-arginine and endothelin receptor antagonist bosentan counteract hemodynamic effects of modified hemoglobin.

Pyridoxalated hemoglobin polyoxyethylene conjugate (PHP), a nitric oxide scavenger, causes systemic and pulmonary vasoconstriction in normal and septic sheep. We studied the effect of L-arginine and the endothelin-1 (ET-1) antagonist bosentan on the PHP response to determine whether the PHP-induced vasoconstriction resulted predominantly from the action of ET-1 or solely from removal of NO. After 24 h of carrier solution (nonseptic sheep), sheep received PHP (20 mg/kg/h; n = 5), PHP plus L-arginine (at 28 h, 100 mg/kg bolus and 500 mg/kg for 1 h) plus bosentan (at 32 h, 10 mg/kg; n = 6), and only L-arginine and bosentan (n = 5). These protocols were repeated after 24 h of Pseudomonas aeruginosa (S, 6x10(6) colony-forming units/kg/h). PHP induced vasoconstriction in septic and nonseptic sheep for the duration of its infusion. In nonseptic sheep, neither L-arginine nor bosentan significantly lowered systemic (SVRI) and pulmonary (PVRI) vascular resistance and did not antagonize the PHP-induced vasoconstriction. During sepsis, SVRI fell and cardiac index (CI) rose. L-arginine and bosentan further decreased SVRI (L-arginine: 34+/-2%*, p<.05; bosentan: 35+/-5%*, p<.05) and PVRI (L-arginine: 28+/-2%*, p<.05; bosentan: 33+/-7%*, p<.05) and increased CI (L-arginine: 29+/-4%*, p<.05; bosentan: 11+/-5%, NS). Both agents antagonized the PHP-induced vasoconstriction lowering SVRI (L-arginine: 29+/-3%*, p<.05; bosentan: 26+/-5%*, p<.05) and PVRI (L-arginine: 27+/-4%*, p<.05; bosentan: 32+/-4%*, p<.05) to levels before PHP administration. Plasma ET-1 levels increased during sepsis (from 9.8+/-.2 to 15.6+/-.7* pg/mL, p<.05) and fell during PHP infusion (to 9.7+/-1.6* pg/mL, p<.05). In nonseptic sheep, ET-1 levels decreased during PHP (from 8.5+/-.6 pg/mL to 5.9+/-.6*, p<.05). Bosentan increased ET-1 levels 2.7 times higher in septic than in nonseptic sheep. We conclude that during sepsis, the NO scavenger PHP unmasks an underlying ET-1 mediated vasoconstriction, and its effect is antagonized by L-arginine and bosentan.

Animals↗
PubMed1995

Protective effects of non-peptide endothelin receptor antagonist bosentan on myocardial ischaemic and reperfusion injury in the pig.

OBJECTIVE: The aim was to investigate the effects of the non-peptide endothelin receptor antagonist bosentan (Ro 47-0203) on haemodynamic variables, infarct size, myocardial overflow, and tissue content of endothelin-like immunoreactivity (ET-LI) during ischaemia and reperfusion in anaesthetised pigs, and to study the inhibitory effect of bosentan on ET-1 induced coronary constriction in vitro. METHODS: Ischaemia was induced by ligation of the left anterior descending coronary artery for 45 min, followed by 4 h of reperfusion. Bosentan was given either intravenously (5 mg.kg-1) 15 min before ischaemia or as a 25 min local coronary venous retroinfusion (10(-4) M) starting at 30 min of ischaemia. ET-LI was analysed in myocardial tissue and in plasma from the anterior interventricular coronary vein and aorta. The effect of bosentan on endothelin-1 induced vasoconstriction was evaluated in isolated diagonal branches of left anterior descending coronary artery. RESULTS: Intravenous bosentan slightly reduced arterial blood pressure (P < 0.05) but did not affect basal coronary vascular resistance. Local retroinfusion of bosentan did not change blood pressure. Intravenous and retroinfused bosentan significantly reduced infarct size by 58% and 48% respectively (P < 0.01) and enhanced the recovery of coronary blood flow by 65-90% compared to vehicle treated controls at the end of 4 h reperfusion. The basal plasma levels of ET-LI and the myocardial overflow of ET-LI during reperfusion increased twofold after bosentan. A threefold increase in the concentration of ET-LI was observed in the ischaemic/reperfused myocardium and this enhancement was significantly attenuated by bosentan. Bosentan effectively antagonised the endothelin-1 induced but not the serotonin induced, contractions of isolated coronary arteries and reversed the established contraction induced by endothelin-1. CONCLUSIONS: The non-peptide endothelin receptor antagonist bosentan markedly protects the myocardium from ischaemia/reperfusion injury and improves blood flow to the reperfused area, indicating the involvement of endogenous endothelin-1 and the therapeutic value of bosentan in the treatment of ischaemia/reperfusion injury.

Animals↗
PubMed1999

The effect of bosentan on the pharmacokinetics of digoxin in healthy male subjects.

AIMS: To investigate the effect of multiple oral dose treatment with the endothelin receptor antagonist bosentan on the pharmacokinetics of digoxin in healthy subjects. METHODS: This was an open-label, randomized, two-way crossover study in 18 evaluable young male subjects. They received, on two occasions which were separated by at least 2 weeks washout period, 0.375 mg digoxin once daily for 13 days following a loading dose of 0.375 mg given twice on the day before the once daily dosing regimen started. On one occasion treatment with 500 mg bosentan twice daily was started on the eighth day of digoxin treatment and continued for 1 week. Serum concentrations of digoxin were determined up to 24 h postdose on day 8 (first day of bosentan treatment) and day 14 (last day of bosentan treatment) of the digoxin treatment period. Plasma concentrations of bosentan were measured at two time points after the first bosentan dose and up to 12 h after the last morning dose of bosentan. Safety was assessed by adverse events, clinical laboratory tests, blood pressure and pulse rate measurements and ECG recordings. RESULTS: Steady-state of digoxin was always achieved after 7 days of treatment. Serum concentrations of digoxin were within the usual therapeutic range. Average steady-state Cmax and Ctr were 2-2.1 microg l-1 and 0.65-0.69 microg l-1, respectively, when given alone. Bosentan did not lead to statistically significant changes in Cmax and Ctr of digoxin. AUC (0,24h) of digoxin, however, was slightly reduced after 1 week of treatment with bosentan. The reduction was 12% on average with a narrow 95% confidence interval of 0-23%. Bosentan pharmacokinetic parameters after 1 week of treatment were as expected with a mean Cmax of 3260 microg l-1 and a mean AUC (0, 12h) of 12 600 microg l-1 h. CONCLUSIONS: Treatment with bosentan 500 mg twice daily for 1 week did not show clinically relevant effects on the pharmacokinetics of digoxin in healthy human subjects

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions.

BACKGROUND: During clinical trials bosentan, the first orally active endothelin receptor antagonist, caused asymptomatic transaminase elevations in some patients. In this study we investigated whether inhibition of the hepatocanalicular bile salt export pump (rodents, Bsep; humans, BSEP ABCB11) could account for bosentan-induced liver injury. METHODS: We reanalyzed the safety database of the bosentan trials for cholestatic liver injury, determined the cholestatic potency of bosentan in the rat, and studied the effects of bosentan and its metabolites on Bsep-mediated taurocholate transport in vitro. RESULTS: Bosentan caused dose-dependent and reversible liver injury in 2% to 18% of patients and caused a significant increase of serum bile salt levels (P <.01). Concomitant administration of glyburide (INN, glibenclamide) enhanced the cholestatic potency of bosentan. Similar effects were seen in rats, in which serum bile salt levels were increased by glyburide less than by bosentan, which increased the levels less than a combination of bosentan and glyburide. In vitro, Bsep-mediated taurocholate transport was inhibited by bosentan (inhibition constant, approximately 12 micromol/L) and metabolites (inhibition constant, approximately 8.5 micromol/L for metabolite Ro 47-8634). CONCLUSIONS: These results indicate that bosentan-induced liver injury is mediated, at least in part, by inhibition of Bsep/BSEP-causing intracellular accumulation of cytotoxic bile salts and bile salt induced liver cell damage. The data further emphasize the pathophysiologic importance of drug-Bsep interactions in acquired forms of cholestatic liver injury.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension.

AIMS: To determine whether bosentan decreases the plasma concentration of sildenafil in patients with pulmonary arterial hypertension. METHODS: Ten patients (aged 39-77 years) with pulmonary arterial hypertension in WHO functional class III received bosentan 62.5 mg twice daily for 1 month, then 125 mg twice daily for a second month. Sildenafil 100 mg was given as a single dose before starting bosentan (visit 1) and at the end of each month of bosentan treatment (visits 2 and 3). Sildenafil and its primary metabolite, desmethylsildenafil, were measured in plasma at 0 h and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 h using liquid chromatography-tandem mass spectrometry. Statistical analysis was by repeated measures anova, using log transformed data where appropriate. RESULTS: Treatment with bosentan 62.5 mg twice daily for 4 weeks was associated with a two-fold increase in sildenafil clearance/F and a 50% decrease in the AUC (P < 0.001). Increasing the dose of bosentan to 125 mg twice daily led to a further increase in sildenafil oral clearance and decrease in the AUC (P < 0.001 vs. 62.5 mg bosentan). The ratio of AUC on bosentan treatment relative to that of visit 1 was 0.47 [95% confidence interval (CI) 0.36, 0.61] for visit 2 and 0.31 (95% CI 0.23, 0.41) for visit 3 (P < 0.001). Sildenafil C(max) fell from 759 ng ml(-1) on visit 1 to 333 ng ml(-1) on visit 3 (P < 0.01) and there was a significant decrease in the plasma half-life of sildenafil on the higher bosentan dose (P < 0.05). The AUC and plasma half-life of desmethylsildenafil was also decreased by bosentan in a dose-dependent manner (P < 0.01). CONCLUSIONS: Bosentan significantly decreases the plasma concentration of sildenafil when coadministered to patients with pulmonary hypertension.

Adult↗
PubMed1999

Endothelin antagonism with bosentan: a review of potential applications.

Endothelin receptor antagonists have been proposed for the treatment of a variety of disorders in which the endothelins may act as pathogenic mediators, such as congestive heart failure, systemic and pulmonary hypertension, and cerebral vasospasm. Bosentan (Ro 47-0203) is a nonpeptide competitive antagonist, which can be a good tool for studying the endothelin system because it may be administered either acutely or chronically. It is specific for the endothelin system and blocks the actions of endothelin at both mammalian receptors (A and B). In experimental models of heart failure bosentan acts as a vasodilator and neurohormonal blocker that improves overall left ventricular performance and reduces renal dysfunction. Furthermore, in chronic studies, bosentan attenuates cardiac remodeling and significantly improves survival. In patients with chronic heart failure bosentan produces pulmonary and systemic vasodilation and may enhance conventional treatment with angiotensin-converting enzyme inhibitors. Long-term studies are being conducted to characterize the full therapeutic potential of bosentan in chronic heart failure. In experimental models bosentan reverses established pulmonary hypertension. Preclinical efficacy has also been demonstrated in essential hypertension, where bosentan can reduce blood pressure and end-organ damage. Clinical trials in hypertensive patients indicate that bosentan reduces blood pressure without heart rate increase or neurohumoral stimulation. Finally, bosentan is being considered for the treatment of cerebral vasospasm following subarachnoid hemorrhage. Bosentan reverses experimentally induced vasospasm of the basilar artery, and preliminary trials indicate that it can increase cerebral blood flow after aneurysmal subarachnoid hemorrhage.

Animals↗
PubMed2000

Differential effects of the mixed ET(A)/ET(B)-receptor antagonist bosentan on endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin release.

Endothelins are a family of potent endogenous mediators that have been implicated in a number of airway and other diseases. Recently, the non-peptide mixed ET(A)/ET(B) endothelin receptor antagonist bosentan has been successfully tested in the treatment of cardiovascular diseases. It was the aim of the present study to characterize the effects of bosentan on the pulmonary actions of endothelin- (ET-1), endothelin-3 (ET-3) and the ET(B)-receptor agonist IRL1620 in the isolated perfused and ventilated rat lung (IPL) and in precision-cut lung slices (PCLS). In the IPL, bosentan completely prevented the IRL1620-induced vasoconstriction (IC50 3 microM). The inhibition by bosentan of ET-1-elicited vasoconstriction showed a biphasic course, reflecting the inhibition of ET(A)-and ET(B)-mediated vasoconstriction (IC50 0.2 microM and 19 microM, respectively). In addition, bosentan prevented the ET-1- (IC50 6 microM) and IRL1620-induced (IC50 3 microM) prostacyclin release. Bosentan also completely prevented the bronchoconstriction induced by IRL1620 in the IPL (IC50 20 microM) and in PCLS (IC50 13 microM). In PCLS, the pD2-values were ET-1 7.20+/-0.23, ET-3 7.51+/-0.27 and IRL1620 7.33+/-0.29. Bosentan at 100 microM caused a rightward shift of the concentration-response curve of ET-1, ET-3 and IRL1620 by a factor of 5, 46 and 64, respectively. In all cases the slope of the Schild regression was lower than unity, disregarding a simple interaction of bosentan with one receptor. With respect to ET-1-induced bronchoconstriction, in the IPL bosentan in concentrations of up to 10 microM aggravated ET-1-induced bronchoconstriction probably due to the blockade of bronchodilatory ET(A)-receptors (IC50 0.3 microM) and even at 100 microM showed only very little protection from ET- -induced bronchoconstriction in the IPL and in the PCLS. The similar IC50-values for ET-1-induced vasoconstriction and bronchodilation suggest that only one type of ET(A)-receptor is involved. The differing IC50-values between IRL1620-induced bronchoconstriction and prostacyclin release, the slope of the Schild regression and the failure of bosentan to prevent the ET-1-induced bronchoconstriction suggest a complex interaction between the known ET-receptors or the existence of unknown ET(B)-receptor subtypes.

Animals↗
PubMed2002

Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole.

AIMS: The present study was conducted to characterize the single- and multiple-dose pharmacokinetics of bosentan, a dual endothelin receptor antagonist, and to investigate a possible pharmacokinetic interaction with ketoconazole. METHODS: In a randomized, two-way crossover study, 10 healthy male subjects received treatments A and B. Treatment A consisted of a single dose of 62.5 mg bosentan on day 1 followed by 62.5 mg twice daily for 5.5 days. Treatment B consisted of bosentan (62.5 mg twice daily) for 5.5 days plus concomitant ketoconazole (200 mg once daily) for 6 days. Plasma concentrations of bosentan and its three metabolites were measured on days 1 and 7 of treatment A and on day 6 of treatment B. RESULTS: Bosentan was absorbed and eliminated with a tmax of 4.5 h (range 3.5-6.0 h) and a t(1/2) of 5.4 h (95% CI; 4.5, 6.6). Upon multiple dosing, the exposure to bosentan was reduced by 33% without change in tmax and t(1/2). Concomitant administration of ketoconazole increased the Cmax and AUC of bosentan 2.1- (95% CI; 1.5, 2.7) and 2.3-fold (95% CI; 1.8, 2.9), respectively. Exposure to the metabolites was low and represented less than 25% of that to bosentan both after single and multiple doses. In the presence of ketoconazole, formation of the metabolites was inhibited. DISCUSSION: The multiple-dose pharmacokinetics of bosentan are consistent with the phenomenon of auto-induction. In the presence of CYP3A4 inhibitors, bosentan concentrations may be increased 2-fold.

Adult↗
PubMed2002

In vivo and in vitro studies exploring the pharmacokinetic interaction between bosentan, a dual endothelin receptor antagonist, and glyburide.

BACKGROUND: In a clinical trial with patients with chronic heart failure, a higher incidence of elevated levels of liver transaminases was observed during concomitant treatment with bosentan, a dual endothelin receptor antagonist, and glyburide (INN, glibenclamide), a sulfonylurea-type antidiabetic drug, than with treatment with bosentan alone. This study was conducted to investigate a possible pharmacokinetic interaction between bosentan and glyburide. METHODS: In a randomized, 2-way crossover study, 12 healthy volunteers received treatments A and B. Treatment A consisted of 125 mg bosentan twice a day for 10 days plus concomitant 2.5 mg glyburide twice a day on days 6 to 10. Treatment B consisted of 2.5 mg glyburide twice a day for 10 days plus concomitant 125 mg bosentan twice a day on days 6 to 10. Plasma concentrations of bosentan and its metabolites and of glyburide were measured on days 5 and 10 of treatment A and treatment B, respectively. RESULTS: Bosentan reduced the area under the concentration-versus-time curve of glyburide approximately 40% (P <.05). Glyburide decreased the area under the concentration-versus-time curve of bosentan and its metabolites 20% to 30% (P <.05). Results of in vitro experiments showed that glyburide is metabolized by cytochrome P450 (CYP) 2C9, 2C19, and 3A4. No interaction was observed on the level of serum protein binding. CONCLUSIONS: The plasma levels of both bosentan and glyburide were reduced after concomitant administration. This finding is consistent with a CYP3A4-inducing potential of both drugs. The observed pharmacodynamic interaction between bosentan and glyburide in patients with chronic heart failure cannot be explained by a pharmacokinetic interaction.

Adolescent↗
PubMed2003

Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin.

BACKGROUND: In vitro, bosentan has been shown to be a mild inducer of cytochrome P450 (CYP) 2C9 and 3A4. PURPOSE: To investigate in vivo the mutual pharmacokinetic interactions between bosentan and simvastatin, a CYP3A4 substrate. METHODS: Nine healthy male subjects were treated in a three-period randomised crossover study with: (A) bosentan 125 mg twice daily for 5.5 days; (B) simvastatin 40 mg once daily for 6 days; and (C) bosentan 125 mg twice daily and simvastatin 40 mg once daily for 5.5 and 6 days, respectively. Plasma concentration-time profiles of bosentan and its metabolites (treatments A and C) and simvastatin and beta-hydroxyacid simvastatin (treatments B and C) were determined on day 6. RESULTS: Steady-state conditions for bosentan and its metabolites were attained on day 4 of treatment. The pharmacokinetic parameters of bosentan and its metabolites were not influenced by concomitant treatment with simvastatin: areas under the plasma concentration-time curve over one administration interval of 12 hours (AUC(tau)) [geometric mean and 95% CI] were 4586 (3719-5656) and 4928 (3945-6156) micro g * h/L. In contrast, bosentan significantly reduced exposure to simvastatin and beta-hydroxyacid simvastatin by 34 and 46%, respectively. AUC(tau) values for simvastatin were 30.5 (23.1-40.2) and 20.0 (15.9-25.1) micro g * h/L and for beta-hydroxyacid simvastatin 43.0 (32.1-57.8) and 23.4 (16.7-32.6) micro g * h/L in treatments B and C, respectively. CONCLUSIONS: Concomitant treatment with bosentan reduces the exposure to simvastatin and beta-hydroxyacid simvastatin by approximately 40%, indicating that in vivo bosentan is also a mild inducer of CYP3A4.

Adult↗
PubMed2006

Improvement in cardiac function of diabetic rats by bosentan is not associated with changes in the activation of PKC isoforms.

We previously demonstrated that chronic treatment with the mixed endothelin A and B (ET(A) and ET(B)) receptor blocker bosentan improved isolated working heart function in streptozotocin (STZ) diabetic rats. Endothelin-1 (ET-1) peptide levels, ET-1 mRNA and ET(A) and ET(B) receptor mRNA were all increased in diabetic hearts, but were unaffected by bosentan treatment, indicating that the beneficial effects of bosentan on heart appear to be on downstream effectors of ET-1 and ET receptors rather than the ET-1 system itself. Stimulation of ET-1 receptors leads to increased activation of protein kinase C (PKC), which is associated with PKC translocation from the cytosol to the membrane. Persistent activation of specific PKC isoforms has been proposed to contribute to diabetic cardiomyopathy. The purpose of this study was to determine whether chronic treatment with bosentan influences the activation of PKC isoforms in hearts from diabetic rats. Male Wistar rats were divided into four groups: control, bosentan-treated control, diabetic, and bosentan-treated diabetic. Diabetes was induced by the intravenous injection of 60 mg/kg streptozotocin. One week later, treatment with bosentan (100 mg/kg/day) by oral gavage was begun and continued for 10 weeks. The heart was then removed, homogenized, separated into soluble (cytosolic) and particulate (membrane) fractions and PKC isoform content in each fraction was determined by Western blotting. PKC alpha, beta2, delta, epsilon and zeta were all detected in hearts from both control and diabetic rats. However, no change in the levels or distribution between the soluble and particulate fractions of any of these isoforms could be detected in chronic diabetic hearts compared to control, whether untreated or treated with bosentan. These observations indicate that bosentan does not improve cardiac performance in STZ diabetic rats by affecting the activation of PKC isoforms.

Animals↗
PubMed1995

Beneficial effects of the endothelin receptor antagonist bosentan on myocardial and endothelial injury following ischaemia/reperfusion in the rat.

The effects of bosentan, a nonpeptide endothelin receptor antagonist, on endothelin-induced changes in coronary flow and myocardial ischaemic and reperfusion injury were investigated in the Langendorff perfused rat isolated heart. Endothelin-1 (0.012-0.4 nmol) evoked dose-dependent reduction in coronary flow, which was attenuated by bosentan (1.0-10 microM) in a concentration-related fashion. The inhibitory effect of bosentan lasted more than 30 min. The endothelin ETB receptor agonist Suc-[Glu9,Ala11,15]endothelin-1-(8-21) (IRL 1620) increased coronary flow in the absence but not in the presence of bosentan. In hearts subjected to 30 min of global ischaemia followed by 30 min of reperfusion, the recoveries of the left ventricular developed pressure, dP/dtmax, and coronary flow were significantly larger in a group given bosentan 10 microM at the start of ischaemia (92 +/- 7%, 98 +/- 8% and 83 +/- 5%, respectively) than in a vehicle-treated group (70 +/- 4%, 70 +/- 6% and 42 +/- 2%, respectively) at the end of the reperfusion period. During the reperfusion period, left ventricular end diastolic pressure was significantly lower in the bosentan group than in the vehicle group. The area of no-reflow in the bosentan group was 7 +/- 3% of left ventricle compared to 21 +/- 2% in the vehicle group (P < 0.01). Acetylcholine-induced endothelium-dependent vasodilatation was significantly reduced after ischaemia and reperfusion in the vehicle group but not in the bosentan group. It is concluded that bosentan attenuates the coronary vasoconstrictor effect elicited by endothelin and reduces ischaemia/reperfusion-induced myocardial and endothelial injury in the rat isolated heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Effects of long-term bosentan in children with pulmonary arterial hypertension.

OBJECTIVES: This study investigated the long-term outcome of children with pulmonary arterial hypertension (PAH) treated with bosentan therapy, with or without concomitant prostanoid therapy. BACKGROUND: Bosentan, an oral endothelin ET(A)/ET(B) receptor antagonist, improves hemodynamics and exercise capacity in adults with PAH; however, limited data are available on its long-term effects in children. METHODS: In this retrospective study, 86 children with PAH (idiopathic, associated with congenital heart or connective tissue disease) started bosentan with or without concomitant intravenous epoprostenol or subcutaneous treprostinil therapy. Hemodynamics, World Health Organization (WHO) functional class, and safety data were collected. RESULTS: At the cutoff date, 68 patients (79%) were still treated with bosentan, 13 (15%) were discontinued, and 5 (6%) had died. Median exposure to bosentan was 14 months. In 90% of the patients (n = 78), WHO functional class improved (46%) or was unchanged (44%) with bosentan treatment. Mean pulmonary artery pressure and pulmonary vascular resistance decreased (64 +/- 3 mm Hg to 57 +/- 3 mm Hg, p = 0.005 and 20 +/- 2 U x m2 to 15 +/- 2 U x m2, p = 0.01, respectively; n = 49). Kaplan-Meier survival estimates at one and two years were 98% and 91%, respectively. The risk for worsening PAH was lower in patients in WHO functional class I/II at bosentan initiation than in patients in WHO class III/IV at bosentan initiation. CONCLUSIONS: These data suggest that bosentan, an oral endothelin ET(A)/ET(B) receptor antagonist, with or without concomitant prostanoid therapy, is safe and efficacious for the treatment of PAH in children.

Adolescent↗
PubMed1995

Differential effects of a novel non-peptide endothelin receptor antagonist (bosentan) in rat liver and vasculature.

1. We studied the effects of the non-selective, non-peptide, orally active endothelin (ET) receptor antagonist bosentan (Ro 47-0203) on rat hepatic and mesenteric vascular membrane 125I-ET-1 binding characteristics in vitro and ex vivo (after bosentan by gavage in vivo). 2. Bosentan caused a concentration-dependent competitive inhibition of 125I-ET-1 binding to female rat mesenteric vascular (predominantly ETA receptors) and hepatic (predominantly ETB receptors) membranes in vitro and ex vivo. 3. The time course of the inhibition of binding ex vivo after administration of bosentan in vivo was 1-4h for mesenteric vascular (predominantly ETA receptors) binding and 1-16h for hepatic (predominantly ETB receptors) binding. 4. The time course of displacement of 125I-ET-1 binding from mesenteric vascular and hepatic membranes by bosentan in vitro was similar. 5. Since bosentan is significantly excreted by the liver, the prolonged hepatic 125I-ET-1 binding by bosentan presumably represents hepatic accumulation of bosentan, which may have implications for bosentan antagonizing the actions of ET in the liver.

Animals↗
PubMed2002

Bosentan therapy for pulmonary arterial hypertension.

BACKGROUND: Endothelin-1 is a potent vasoconstrictor and smooth-muscle mitogen. In a preliminary study, the orally administered dual endothelin-receptor antagonist bosentan improved exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary arterial hypertension. The present trial investigated the effect of bosentan on exercise capacity in a larger number of patients and compared two doses. METHODS: In this double-blind, placebo-controlled study, we randomly assigned 213 patients with pulmonary arterial hypertension (primary or associated with connective-tissue disease) to receive placebo or to receive 62.5 mg of bosentan twice daily for 4 weeks followed by either of two doses of bosentan (125 or 250 mg twice daily) for a minimum of 12 weeks. The primary end point was the degree of change in exercise capacity. Secondary end points included the change in the Borg dyspnea index, the change in the World Health Organization (WHO) functional class, and the time to clinical worsening. RESULTS: At week 16, patients treated with bosentan had an improved six-minute walking distance; the mean difference between the placebo group and the combined bosentan groups was 44 m (95 percent confidence interval, 21 to 67; P<0.001). Bosentan also improved the Borg dyspnea index and WHO functional class and increased the time to clinical worsening. CONCLUSIONS: The endothelin-receptor antagonist bosentan is beneficial in patients with pulmonary arterial hypertension and is well tolerated at a dose of 125 mg twice daily. Endothelin-receptor antagonism with oral bosentan is an effective approach to therapy for pulmonary arterial hypertension.

Administration, Oral↗