Impact of Physical Exercise on Levodopa Therapy Across Parkinson's Disease Stages

Abstract

Background: Levodopa is the gold standard of treatment in Parkinson's disease (PD). Its clinical effect changes as the disease progresses. Wearing off is a frequent first manifestation of motor fluctuations. Some patients with advanced PD report faster wearing off after physical exercise.

Objective: The aim was to assess if pharmacokinetics of levodopa is influenced by physical exercise in patients with different disease advancement.

Methods: 22 patients with PD (12 untreated with levodopa and 10 with motor fluctuations) and 7 healthy controls (HC) were included. Plasma samples were collected at 9 fixed timepoints following administration of levodopa/benserazide 200/50 mg for two days: rest day and standardized physical exercise day. Clinical assessment with Unified Parkinson Disease Rating Scale part III (UPDRS III) was performed in fixed timepoints. Liquid chromatography-tandem mass spectrometry was used to measure levodopa concentrations.

Results: No differences between the HC, levodopa naïve and advanced PD groups were observed regarding selected pharmacokinetic parameters. In advanced PD and HC no differences in pharmacokinetic parameters of levodopa with and without effort were observed. In levodopa naïve PD group higher mean residence time after rest than after exercise (168.9±48.3 min vs. 145.5±50.8 min; p = 0.026) was observed. In advanced PD group higher UPDRS III score (14.45±5.5 versus 20.9±6.1 points, p = 0.04) was observed after exercise.

Conclusions: The deterioration of motor status of advanced PD patients after physical effort is not reflected by changes in pharmacokinetics but rather mediated by central mechanisms.

Keywords: Levodopa; Parkinson’s disease; exercise; pharmacokinetics.

Fig. 1

Selected pharmacokinetic parameters comparison between study groups. A) Statistically significant differences in the MRT parameter with and without effort were observed for the levodopa nïve Parkinson’s disease (LNPD) group. No significant difference was observed in advanced Parkinson disease (APD) group and healthy control (HC). B) Influence of exercise on the UPDRS III score after 180 min. In APD group UPDRS III score was significantly higher at 180 min during physical exercise day than during rest day. HC, healthy control; LNPD, levodopa naïve Parkinson’s Disease; APD, advanced Parkinson’s disease; MRT, mean residence time; UPDRS, Unified Parkinson Disease Rating Scale-part III; min, minutes. Significant differences are marked with *. Significant p-value is considered < 0.05.

Fig. 2

A) Heat map visualization of differences in pharmacokinetic parameters in three different groups. The deeper the blue color, the lower value of the parameter compared to other patients analyzed. The deeper the red color, the higher the level. The parameters with similar behavior across the samples were clustered. Scores Plot B and Loading Plot C illustrate Principal Component Analysis of pharmacokinetic parameters after levodopa administration to treated and non-treated patients. T_max, Time to peak drug concentration; t_1/2, half-life time; C_max, maximum serum concentration; AUC 0-inf- the area under the concentration-time curve from dosing (time 0) to infinity; MRT 0-inf, mean residence time from dosing (time 0) to infinity t; DIFF, relative difference between a parameter with and without physical effort; Vz, volume of distribution; Cl, clearance; PE, Physical exercise day, RD, rest day.