Bosentan

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals

Pharmaceuticals -> Antihypertensives

3.7

1.99

Poorly soluble in water (1.0 mg/100 ml) and in aqueous solutions at low pH (0.1 mg/100 ml at pH 1.1 and 4.0; 0.2 mg/100 ml at pH 5.0). Solubility increases at higher pH values (43 mg/100 ml at pH 7.5).

9.04e-03 g/L

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Cardiovascular Agents; Endothelin Receptor Antagonists; Vasodilator Agents

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Danger

H302 (40%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P264, P270, P273, P280, P301+P317, P318, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 5 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Bosentan is associated with elevations in serum aminotransferase levels above three times the upper limit of the normal range (ULN) in 3% to 18% of patients, averaging 7.6% using currently recommended doses. The enzyme elevations are usually self-limited and are rarely accompanied by symptoms, but can be more marked and persist and require dose reduction or discontinuation (in 3% to 4% of patients). Monthly monitoring of serum aminotransferase levels is recommended, with discontinuation for levels above 8 times the ULN or for values above 5 times the ULN that persist. There have also been rare reports of clinically apparent liver injury with jaundice associated with bosentan use. The onset of illness was usually within 1 to 6 months of starting bosentan, but cases arising during chronic therapy have also been described (Case 1). The enzyme pattern has typically been hepatocellular or mixed. Immunoallergic features are usually not present and autoantibodies are usually absent or present in low titer. Some cases have been severe and fatalities have been reported, but there have been no published reports of chronic hepatitis or vanishing bile duct syndrome attributed to bosentan. Autoimmune and immunoallergic features are usually not present.

The most frequently observed adverse effect of bosentan overdose is headache. In a cyclosporine A interaction study, administration of 500 mg and 1,000 mg of bosentan twice daily in combination with cyclosporine A resulted in a 30-fold increase in trough plasma concentrations, leading to severe headache, nausea, and vomiting. No serious adverse events were reported. Additional findings included hypotension and tachycardia.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Bosentan

vMost-DILI-concern

7

Box warning

DOI:10.1016/j.drudis.2016.02.015

C02KX01

C - Cardiovascular system

QC - Cardiovascular system

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.

Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET_A and ET_B receptors in the endothelium and vascular smooth muscle. It displays a slightly higher affinity towards ET_A receptors than ET_B receptors. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ET_A and ET_B.

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.

Bosentan has known human metabolites that include Hydroxy Bosentan and 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-hydroxyphenoxy)-[2,2-]bipyrimidinyl-4-yl]-benzenesulfonamide.

XUL93R30K2

BOSENTAN ANHYDROUS

Established Pharmacologic Class [EPC] - Endothelin Receptor Antagonist

Mechanisms of Action [MoA] - Endothelin Receptor Antagonists

Mechanisms of Action [MoA] - Cytochrome P450 3A Inducers

Mechanisms of Action [MoA] - Cytochrome P450 2C9 Inducers

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Compounds and drugs that bind to and inhibit or block the activation of ENDOTHELIN RECECPTORS.

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

Bosentan is eliminated by biliary excretion following metabolism in the liver.

18 L

4 L/h [patients with pulmonary arterial hypertension]