The metabolism of the dual endothelin receptor antagonist macitentan in rat and dog.
1. The metabolism of the endothelin receptor antagonist macitentan has been characterized in bile duct-cannulated rats and dogs. 2. In both species, macitentan was metabolized along five primary pathways, i.e. conjugation with glucose (M9), oxidative depropylation (M6), aliphatic hydroxylation (M7), oxidative cleavage of the ethylene glycol linker (M4) and hydrolysis of the sulfamide moiety (M3). Most of the primary metabolites underwent subsequent biotransformation including conjugation with glucuronic acid or glucose, hydrolysis of the sulfamide group or secondary oxidation of the ethylene glycol moiety. 3. Though there were species differences in their relative importance, all metabolic pathways were present in rat and dog. The depropylated M6 was the only metabolite present in plasma of both species. 4. Metabolism was a prerequisite for macitentan excretion as relevant amounts of parent drug were neither detected in bile nor urine. Biliary excretion was the major elimination pathway, while renal elimination was of little importance.
a Department of Non-Clinical Drug Metabolism and Pharmacokinetics and.
Alexander
A
Treiber
a Department of Non-Clinical Drug Metabolism and Pharmacokinetics and.
Tommaso
T
Miraval
b Department of Medicinal Chemistry , Actelion Pharmaceuticals Ltd , Allschwil , Switzerland.
Martin H
MH
Bolli
b Department of Medicinal Chemistry , Actelion Pharmaceuticals Ltd , Allschwil , Switzerland.
Jacques-Alexis
JA
Funel
a Department of Non-Clinical Drug Metabolism and Pharmacokinetics and.
Jerome
J
Segrestaa
a Department of Non-Clinical Drug Metabolism and Pharmacokinetics and.
Swen
S
Seeland
D000818:Animals; D001652:Bile Ducts / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D065128:Endothelin Receptor Antagonists / Q000493:pharmacokinetics* / Q000652:urine; D019855:Ethylene Glycol / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006900:Hydroxylation; D008297:Male; D053858:Metabolic Networks and Pathways; D008862:Microsomes, Liver / Q000378:metabolism; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000652:urine
D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; D019855:Ethylene Glycol; D005947:Glucose; C533860:macitentan
Endothelin receptor antagonist; macitentan; metabolism in rat and dog