Bosentan Chemische Eigenschaften,Einsatz,Produktion Methoden
Chemische Eigenschaften
Pale Yellow to Off-White Solid
Verwenden
A mixed endothelin receptor antagonist. Used as a vasodilator. Antihypertensive.
Allgemeine Beschreibung
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.
Pharmakokinetik
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.
Nebenwirkungen
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.
Bosentan Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
