The pharmacokinetics of intravenous and oral levodopa in patients with Parkinson's disease who exhibit on‐off fluctuations.

Abstract

We have studied the clinical effects and pharmacokinetics of levodopa infusions and oral therapy in seven patients with Parkinson's disease. They all showed on‐off fluctuations whilst receiving long‐term treatment with levodopa in combination with a peripheral decarboxylase inhibitor. Intravenous infusion at a constant rate for up to 16 h resulted in a smoother clinical response, and maintained plasma levodopa concentrations within narrower limits compared with conventional oral therapy. Following infusion rates of 32‐80 mg h‐1 (0.5‐1.3 mg kg‐1 h‐1) the plasma concentration associated with optimum therapeutic response lay between 0.3 and 1.6 mg l‐1. There was considerable variation in the oral absorption and elimination of levodopa, both within and between subjects. The concentration of 3‐OMe dopa in plasma hardly increased during each day's levodopa therapy. In all cases levels were greater than the maximum concentrations of levodopa, sometimes by as much as a factor of 10. In contrast to most previous reports on the pharmacokinetics of levodopa, the data presented here are consistent with a two‐compartment kinetic model. It is not known whether the difference in pharmacokinetics is due to chronic therapy or whether it is specific to those patients who show on‐ off phenomena, but such changes might be related in some way to the development of fluctuations in clinical response.

Pharmacokinetics of Levodopa, Carbidopa, and 3-O-Methyldopa Following 16-hour Jejunal Infusion of Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson’s Disease Patients

“…In the present study, 3-OMD showed a very flat pharmacokinetic profile with 16-h LCIG infusion (Fig. 2b) and very low intrasubject variability (6%) and degree of fluctuation (37). Taken together, these results suggest that 16-h LCIG infusion does not alter the 3-OMD/levodopa metabolite/parent exposure ratio at steady state and, therefore, may not adversely impact the brain uptake of levodopa compared to intermittent oral administration.…”

L‐Dihydroxyphenylserine (L‐DOPS): A Norepinephrine Prodrug

“…L-DOPS levels in plasma are roughly similar in magnitude and timing to those reported after administration of levodopa (12,33,55,77). Since LAAAD, which catalyzes the conversion of L-DOPS to NE, is an intracellular enzyme, the approximately simultaneous attainment of peak plasma levels of L-DOPS and of NE indicates rapid intracellular conversion of L-DOPS to NE and rapid exit of the NE from cells into the extracellular fluid.…”

Microdialysis Studies on the Action of Tolcapone on Pharmacologically‐Elevated Extracellular Dopamine Levels in Conscious Rats

“…When levodopa is given with a dopa decarboxylase inhibitor like carbidopa, the majority of surplus L-dopa is metabolized by peripheral COMT (Kuruma et al 1972;Messiha et al 1972;Fahn 1974;Da Prada et al 1984;Mannisto et al 1992b). During the combination therapy, 3-0-methyldopa is the major metabolite (Fahn 1974;Rivera-Calimlim et al 1977;Reilly et al 1980;Da Prada et al 1984;Hardie et al 1986), and the role of COMT inhibitors becomes extremely meaningful. The functional significance of this combination has been nicely demonstrated in the rat lesion model of Parkinson's disease where COMT inhibitors potentiate the effect of levodopa on contralateral turning behaviour ).…”