Metabolic Fate of Pergolide Mesylate (4): Metabolism of 14C-Pergolide Mesylate in Rats and Monkeys.

Abstract

1. After repeated oral administration of 0.06 or 2 mg/kg of PERGOLIDE MESYLATE to male rats, liver microsomal protein content, cytochrome p-450 content, aniline hydroxylase activity and p-nitrophenyl UDP-glucuronyltransferase activity were elevated compared to controls. Aminopyrine N-demethylase activity was higher than controls only in the group receiving 0.06mg/kg dose. 2. After oral administration of 2 mg/kg of 14C-PERGOLIDE MESYLATE, the plasma samples collected at 0.5 ?? 24 hours after dosing contained PERGOLIDE SULFOXIDE and an unknown metabolite, M7, as major metabolites and PERGOLIDE as a minor component. Unknown metabolites, M6 (conjugate of PERGOLIDE or unknown metabolite M10) and M8, as well as PERGOLIDE SULFOXIDE were major metabolites excreted in the urine. PERGOLIDE was a major component excreted in the feces. The bile contained two major unknown metabolites, M6 and M8. Major radioactive spots, corresponding to PERGOLIDE and PERGOLIDE SULFONE, were found in the liver, PERGOLIDE, PERGOLIDE SULFOXIDE and PERGOLIDE SULFONE were found to be major metabolites in the lung. However, in the kidney, PERGOLIDE was the major component at 2 hours after dosing while at 24 hours the major component in the kidney was the unknown metabolite, M5. The relative amounts of metabolites after repeated oral dosing were similar to those observed in the group receiving a single oral dose. 3. PERGOLIDE was a minor component and the unknown metabolites, M8 and M2, were major components in the plasma and urine of male monkeys dosed orally with 2mg/kg of 14C-PERGOLIDE MESYLATE. None of the metabolites found in monkey plasma was present in the form of a conjugate.