The fate of levodopa in rats and man

Although levodopa was introduced almost 30 years ago it still represents the first-choice treatment of Parkinson's disease. However, during long-term administration of the drug approximately 50% of patients suffer from unwanted side-effects such as end-of-dose deterioration or the `on-off' phenomenon. These side effects have been reported to be due to the pharmacokinetics and/or pharmacodynamics of the drug which are complex and at the present time not fully understood. Levodopa has been reported to be absorbed across the intestine by a saturable, active transport system used by other large neutral amino acids and known as the LNAA transport system. Evidence to support this was provided by experiments with inverted segments of rat intestine in-vitro. Uptake of levodopa by the segments was significantly reduced by rendering the tissues anoxic by gassing with N2, in the presence of the large neutral amino acids L-leucine, L-phenylalanine and by the metabolic inhibitor cyanide. The use of inverted gut sacs and isolated brush border membrane vesicles did not prove satisfactory for measuring the active transport system of levodopa absorption. Covalent binding of the drug occurred with the isolated brush border membrane vesicle preparations. Large individual and regional differences were observed in the L-aromatic amino acid decarboxylase (L-AAAD) activity of the rat stomach and intestine in-vitro. Furthermore, large individual differences in L-AAAD activity were observed in biopsy samples obtained from the human gastric and duodenal mucosae. These findings may explain the large individual differences in plasma concentrations often seen following oral administration of levodopa. In addition, the gut flora were found to be capable of extensive metabolism of levodopa. Age was found to be an important determinant of the pharmacokinetics of levodopa when given alone or in conjunction with the peripheral decarboxylase inhibitor carbidopa. Systemic clearance in the elderly was significantly lower than in the young, both in the absence and presence of carbidopa. In the absence of carbidopa the absolute oral bioavailability of levodopa, as assessed by an oral/IV comparison in young and elderly healthy volunteers, was found to be 63% in the elderly, significantly higher than that in the young (41%). In the presence of the decarboxylase inhibitor the age-related difference was abolished, the bioavailability in both groups increasing to 85% and 86% in elderly and young respectively. Levodopa inhibited gastric emptying in young healthy volunteers and resulted in the presence of multiple peaks following oral administration of the drug. Altered gastric emptying may be extremely important in patients suffering from the `on-off' phenomenon because such patients appear to be dependent on constant plasma levels of the drug. (DX88275)