Metabolic Fate of Pergolide Mesylate. (1): Absorption, Distribution, Excretion of 14C-Pergolide Mesylate in Rats and Monkeys after Single Administration.

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The absorption, distribution and excretion of PERGOLIDE MESYLATE have been investigated in rats and monkeys after administration of a single oral dose of 14C-PERGOLIDE MESYLATE labeled on the thiomethylene carbon. 1. Male rats, receiving orally 2 mg/kg of 14C-PERGOLIDE MESYLATE, had maximum blood concentrations of 28 ng-euuivalents/ml of PERGOLIDE 2hr after dosing. Blood levels of radioactivity decreased with a half-life of 45 hours. The concentration of radioactivity in the blood increased in a dose-dependent manner at doses ranging from 1 ?? 5 mg/kg. Female rats dosed orally with 2mg/kg of 14C-PERGOLIDE MESYLATE had blood concentrations similar to those observed in male rats. However, female rats exhibited two peaks of radioactivity at 2 and 24 hours after dosing. Peak blood concentrations of 57ng equivalents/ml of PERGOLIDE were achieved in male rats 30min after intravenous dose of 1mg/kg of 14C-PERGOLIDE MESYLATE. The half-life of radioactivity in the blood, as measured between 0.5 and 4 hours, was 4.0 hours, and 29 hours when measured from 6 ?? 48 hours. In male monkeys, the peak plasma concentrations of 326ng equivalents/ml were observed 1 hour after an oral dose of 2mg/kg of 14C-PERGOLIDE MESYLATE. The half-life of radioactivity was 5.4 hours. 2. Male rats dosed orally with 2mg/kg of 14C-PERGOLIDE MESYLATE excreted 18.2%of the dose in the urine and 75.7% in the feces during 168 hours after dosing. Similar excretion patterns were observed in fasting male rats, female rats, and in male rats receiving either 1 or 5mg/kg of the drug. After intravenous administration of 1mg/kg of 14C-PERGOLIDE MESYLATE, male rats during 168 hours after administration excreted 23.3% and 69.9% of the dose in the urine and feces, respectively. In female rats dosed orally with 2mg/kg of 14C-PERGOLIDE MESYLATE, corresponding excretion was 21.4% and 72.2% of administered dose. Male monkeys, dosed p.o. with 2mg/kg of 14C-PERGOLIDE MESYLATE, excreted 54.3% and 39.4% of the dose in the urine and feces, respectively, during 240 hours after dosing. 3. Bile duct cannulated male and female rats, dosed orally with 2mg/kg of 14C-PERGOLIDE MESYLATE, excreted 17.4% and 16.0% of the dose, respectively, in the bile during 48 hours after dosing. Entero-hepatic circulation was observed after intraduodenal injection of radioactive bile. 4. After oral administration of 2mg/kg of 14C-PERGOLIDE MESYLATE to male rats, high concentrations of radioactivity were noted in the gastro-intestinal tract, liver, kidney and submaxillary gland, while low levels were found in the central nervous system and eyeball. Radioactivity was eliminated slowly from the thyroid gland, spleen, kidney and brown fat.