Key result
Macitentan clears primarily via biliary excretion across five metabolic pathways in preclinical models.
Why the study?
The metabolism of the endothelin receptor antagonist macitentan in bile duct-cannulated rats and dogs was characterized to understand its metabolic pathways and elimination.
Macitentan undergoes extensive metabolism in rats and dogs, primarily eliminated via biliary excretion.
Preclinical macitentan data should not guide human dosing; leaves open interspecies differences requiring clinical pharmacokinetic studies.
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.
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Treiber et al. (2015) studied this question. Macitentan was evaluated on Metabolism pathways and excretion. Macitentan was metabolized along five primary pathways in rats and dogs, with biliary excretion serving as the major elimination pathway.
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