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

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 naive 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 naive 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. Plain language summary Background: Levodopa is an important treatment for Parkinson's disease (PD). As the disease gets worse, levodopa's effects change. A common problem is "wearing off," where the medicine stops working sooner than expected. Some advanced PD patients say this happens faster after they exercise. Study goals: The study aimed to find out if exercise changes how the body processes levodopa in patients at different stages of PD. Methods: Participants: 22 PD patients (12 not yet on levodopa and 10 advanced patients-treated with levodopa with "wearing off") and 7 healthy people. Procedure: Participants took levodopa/benserazide (200/50 mg) on two days: a rest day and an exercise day. Each day blood samples were collected at 9 set times to measure levodopa levels. PD symptoms were assessed using a scale called UPDRS III at specific times. Testing: Levodopa levels in blood were measured using a technique called liquid chromatography-tandem mass spectrometry. Results: No differences: There were no differences in how the body processed levodopa among healthy people, untreated PD patients, and advanced PD patients. Exercise impact: For both healthy people and advanced PD patients, exercise did not change how the body processed levodopa. Untreated patients: In PD patients not yet on levodopa, the medicine stayed in the body longer after rest compared to after exercise. Advanced PD patients: These patients had worse PD symptoms after exercise, but this was not due to changes in how levodopa was processed. Conclusion: The worsening of symptoms in advanced PD patients after exercise is not because of changes in levodopa levels. It likely involves other factors in the brain.