Absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan in healthy male subjects. |
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Authors: | C Weber R Gasser G Hopfgartner |
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Institution: | F. Hoffmann-La Roche Ltd., Clinical Development, Basel, Switzerland. cornelia.weber@roche.com |
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Abstract: | The absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan was investigated in healthy male subjects by administration of 14C-labeled compound. Four subjects received a single oral dose of 500 mg of bosentan (3.7 MBq), and four other subjects received a single i.v. dose of 250 mg of bosentan (3.7 MBq). Radioactivity and concentrations of bosentan and its metabolites were measured in plasma, urine, and feces samples. More than 97% of drug-related material was recovered on average within 3.5 days after oral dosing and within 5 days after i.v. dosing. More than 90% of radioactivity was found in feces after both oral and i.v. dosing. Most of the radioactivity in urine and feces represented bosentan and three metabolites. Ro 48-5033, the major metabolite in plasma, urine, and feces, is the result of hydroxylation at the t-butyl group of bosentan. The two other metabolites Ro 47-8634 and Ro 64-1056 represent minor metabolite species. Ro 47-8634 is the product of O-demethylation of the phenolic methyl ester, and Ro 64-1056 is generated by both demethylation and hydroxylation. The radioactivity in plasma could almost entirely be attributed to bosentan and the two metabolites Ro 48-5033 and Ro 47-8634, whereby both metabolites exhibited much lower plasma levels than bosentan. Hepatic metabolism followed by biliary excretion of the metabolites apparently represents the major pathway of elimination for bosentan in humans. |
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