Dose-dependent pharmacokinetics of laevodopa and its metabolites in the rat

1. Plasma levels of total radioactivity, unchanged laevodopa, dopamine, 3-O-methyldopa and non-amino phenolic acids were measured in rats treated orally with [³H]laevodopa at total laevodopa doses of 1, 10, 20 and 100 mg/kg while the radioactive dose was maintained at 100μCi/kg for all animal groups. 2. Within the dosage range studied, non-linear pharmacokinetics were observed for unchanged laevodopa, non-amino phenolic acids and dopamine but not for 3-O-methyldopa. 3. The area under the plasma concentration-time curve for laevodopa increased exponentially with linear increments in the oral dose. This non-linear increase in laevodopa bioavailability is consistent with the hypothesis that high oral doses of laevodopa are required to saturate gastro-intestinal metabolism of the drug. 4. At the lower doses (1 and 20 mg/kg), only 2-3% of total radioactivity could be attributed to dopamine. At 100 mg/kg, the dopamine metabolite fraction amounted to about 1 /3 of total radioactivity in the plasma.