Bosentan

Absorption

Absolute bioavailability is approximately 50% and food does not affect absorption.

Toxicity

Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support.

Description

Bosentan was introduced in the US as a twice-daily oral treatment for pulmonary arterial hypertension. It can be synthesized in five steps via condensation of diethyl (2- methoxyphenoxy)malonate with pyrimidine-2-carboxamidine to give the precursor of the symmetrical central dichloropyrimidine ring which is then successively treated with the potassium salt of 4-tert-butylbenzenesulfonamide and the sodium salt of ethylene gycol. Bosentan is the first endothelin (ET) receptor antagonist to be launched. ET-1, the most potent endogenous vasoconstrictor known, has been demonstrated to play a major role in the functional and structural changes observed in pulmonary hypertension. Bosentan is a mixed ET_A and ET_B receptor antagonist that inhibits the pulmonary arterial vasoconstricting effect of ET-1 predominantly mediated via ET_A receptors on smooth muscle cells. In a hypoxia-induced model of pulmonary hypertension in rat, it reduced the development of pulmonary hypertension as well as right ventricular hypertrophy and prevented pulmonary arterial remodeling. In clinical trials, patients treated with bosentan showed a 20% increase in exercise capacity compared to placebo as measured by the six minute walk test. Bosentan not only improved the distance walked by patients but also significantly decreased mean pulmonary artery pressure, mean pulmonary vascular resistance, mean capillary wedge pressure and mean right atrial pressure. It demonstrated a beneficial selectivity for the pulmonary vasculature since it had no significant effect on mean aortic blood pressure and systolic vascular resistance. The compound is hepatically metabolized into three major metabolites by CYP3A4 and 2C9 and almost exclusively eliminated in the bile. Although large interspecies differences in systemic plasma clearance was observed (1.5 mL/min/kg in dogs to 72 mL/min/kg in rabbits), a satisfactory systemic clearance (2 mL/min/kg) was measured in human. The most frequent adverse effect was reversible elevation of liver transaminases. This adverse reaction appears to be due to intracellular accumulation of cytotoxic bile salts resulting from inhibition of the hepatocanalicular bile salt export pump by bosentan.

Chemical properties

Pale Yellow to Off-White Solid

Originator

Roche (Switzerland)

The Uses of Bosentan

Bosentan is a mixed endothelin receptor antagonist. Used as a vasodilator. Antihypertensive.

The Uses of Bosentan

A mixed endothelin receptor antagonist. Used as a vasodilator. Antihypertensive.

Background

Bosentan is a dual endothelin receptor antagonist marketed under the trade name Tracleer by Actelion Pharmaceuticals. Bosentan is used to treat pulmonary hypertension by blocking the action of endothelin molecules that would otherwise promote narrowing of the blood vessels and lead to high blood pressure.

Indications

Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms).

What are the applications of Application

Bosentan is a mixed endothelin receptor antagonist

Definition

ChEBI: Bosentan is a sulfonamide, a member of pyrimidines and a primary alcohol. It has a role as an antihypertensive agent and an endothelin receptor antagonist.

Manufacturing Process

4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4- yl]benzenesulphonamide were heated to 100°C, cooled for a further 4 hours, poured on to ice and adjusted to pH 3 with 1 M tartaric acid. The suspension obtained was extracted with ethyl acetate, the organic extracts were combined, washed with water, dried with sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel with CH2Cl2-ethyl acetate 9:1 and yielded 4-t-butyl-N-[6-(2-hydroxyethoxy)-5-(2- methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]benzenesulphonamide as a solid. Sodium salt melted at 195°-198°C.
The 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl)-pyrimidin- 4-yl]benzenesulfonamide was prepared starting from pyrimidine-2- carboxamidine hydrochloride via rac-5-(2-methoxyphenoxy)-2-(pyrimidin-2- yl)tetrahydropyrimidine-4,6-dione and 4,6-dichloro-5-(2-methoxyphenoxy)- 2,2'-bipyrimidine.

brand name

Tracleer (Actelion).

Therapeutic Function

Endothelin receptor antagonist

General Description

Bosentan, N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tertbutyl-benzenesulfonamide (Tracleer, Bozentan), was thefirst endothelin receptor antagonist marketed in the UnitedStates. Bosentan works by competitively blocking the endothelinreceptor subtypes ETA and ETB. In binding to thereceptors, it blocks the effects of endothelin, which includeconstriction of the vascular smooth muscle, which leads tonarrowing of the blood vessels and hypertension. Althoughit is not selective for the ETA receptors, it does have a higheraffinity for that subtype over ETB. However, the clinical significanceof selectivity over preferential receptor bindinghas not been demonstrated. Bosentan is an inducer ofCYP2C9 and CYP3A4, and patients using bosentan must bemonitored for liver toxicity.

Hazard

A reproductive hazard.

Pharmacokinetics

Bosentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects.

Pharmacokinetics

Bosentan is mainly eliminated from the body by hepatic metabolism and subsequent biliary excretion of the metabolites. Three metabolites have been identified, formed by CYP2C9 and CYP3A4. The pharmacokinetics of bosentan are dose-proportional up to 500 mg/day (multiple doses). The pharmacokinetics of bosentan in pediatric patients with PAH are comparable to those in healthy subjects, whereas adult patients with PAH show a twofold increase in clearance. Severe renal impairment and mild hepatic impairment do not have a clinically relevant influence on its pharmacokinetics. Bosentan generally should be avoided in patients with moderate or severe hepatic impairment and/or elevated liver aminotransferases. Inhibitors of CYP3A4 increase the plasma concentration of bosentan as well as cause an increase in the clearance of drugs metabolized by CYP3A4 and CYP2C9 because of induction of these metabolizing enzymes. The possibility of reduced efficacy of CYP2C9 and CYP3A4 substrates coadministered with bosentan is increased. No clinically relevant interaction was detected for P-glycoprotein. Bosentan can increase plasma levels of ET-1.

Clinical Use

Bosentan is an orally administered, nonselective ET-1 receptor antagonist blocking ETA and ETB receptors and is approved for the treatment of patients with PAH. Following oral administration, bosentan attains peak plasma concentrations in approximately 3 hours, with an absolute bioavailability of approximately 50%. Food has no clinically relevant effect on its absorption recommended doses. Bosentan is approximately 98% bound to albumin, with a volume of distribution of 30 L. Its terminal half-life after oral administration is 5.4 hours and is unchanged at steady state.

Side Effects

Adverse effects include hypotension, headache, flushing, increased liver aminotransferases, leg edema, and anemia. Bosentan may cause birth defects and, therefore, is contraindicated in pregnancy. It also can cause liver injury.

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration reduced by rifampicin - avoid. Antidiabetics: increased risk of hepatoxicity with glibenclamide - avoid. Antifungals: fluconazole, ketoconazole and itraconazole cause large increases in concentration of bosentan - avoid. Antivirals: concentration of bosentan increased by lopinavir and ritonavir - consider reducing bosentan dose; telaprevir concentration reduced and bosentan concentration possibly increased; avoid with tipranavir. Ciclosporin: When ciclosporin and bosentan are co-administered, initial trough concentrations of bosentan are 30 times higher than normal. At steady state, trough levels are 3-4 times higher than normal. Blood concentrations of ciclosporin decreased by 50% - avoid. Cytotoxics: concentration of bosutinib possibly reduced - avoid. Guanfacine: concentration of guanfacine possibly reduced - increase guanfacine dose. Lipid lowering agents: concentration of simvastatin reduced by 45% - monitor cholesterol levels and adjust dose of statin. Oestrogens, progestogens and ulipristal: may be failure of contraception - use alternative method.

Metabolism

Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound.

Metabolism

Upon multiple dosing, plasma concentrations of bosentan decrease gradually to 50%-65% of those seen after single dose administration. This decrease is probably due to auto-induction of metabolising liver enzymes. Steadystate conditions are reached within 3-5 days. Bosentan is eliminated by biliary excretion following metabolism in the liver by the cytochrome P450 isoenzymes, CYP2C9 and CYP3A4. Bosentan forms three metabolites and only one of these is pharmacologically active. This metabolite is mainly excreted unchanged via the bile. In adult patients, the exposure to the active metabolite is greater than in healthy subjects. In patients with evidence of the presence of cholestasis, the exposure to the active metabolite may be increased.

storage

Store at +4°C