Is Levodopa Pharmacokinetics in Patients with Parkinson’s Disease Depending on Gastric Emptying?

Abstract

Levodopa uptake from the gastrointestinal tract in patients with Parkinson's disease (PD) can be affected by delayed gastric emptying (GE). This might lead to fluctuating levodopa levels resulting in increased motor fluctuations. Continuous dopaminergic stimulation (CDS) improves motor fluctuations and could be a result of smoothening in levodopa uptake. In this study we wanted to study the levodopa pharmacokinetics peripherally in PD patients with motor fluctuations and investigate the relation between levodopa uptake and GE and the effect of CDS. PD patients with wearing off (group 1) and on-off syndrome (group 2) were included. Breath tests were performed to evaluate the half time (T1/2) of GE. Concomitantly 1 tablet of Madopark  was given and the levodopa concentrations in blood and subcutaneous (SC) tissue were analyzed for both groups. Group 2 was then given a 10-d continuous intravenous levodopa treatment and the tests were repeated. Higher levels of levodopa in group 1 compared to group 2 in blood (p = 0.014) were seen. The GE was delayed in both group 1 (p < 0.001) and group 2 (p < 0.05) compared to a reference group with healthy volunteers with T1/2 median values 105 and 78 min vs. 72 min. There was no difference in GE between the two PD groups (p = 0.220) or in group 2 before and after infusion period (p = 0.861). CDS resulted in lower levodopa levels in blood (p < 0.001) and SC tissue (p < 0.01).In conclusion, PD patients in early complication phase have a more favourable levodopa uptake than patients later in disease. We found delayed GE in PD patients with motor fluctuations but no obvious relation between GE and levodopa uptake or GE and PD stage. The effect of CDS indicates no effect of CDS on the mechanisms of GE but on the mechanisms of levodopa uptake.

Impact of outpatient gastroenterology consult on pharmacotherapy and management of gastrointestinal symptoms in Parkinson’s Disease

“…Interestingly, our study is not the first to suggest that gastric dysmotility may have a more limited role in causing motor fluctuations than previously thought. Tanaka et al found no significant difference in delayed gastric emptying (GE) between PD patients with and without motor fluctuations [25] , and Nord et al found no relation between delayed GE and levodopa uptake [26] . Possibly, other mechanisms of levodopa malabsorption play a larger role, for example: (1) higher relative abundance of certain bacterial populations like gut bacterial tyrosine decarboxylases can cause premature conversion of levodopa to dopamine [27] .…”

Clinical implications of gastric complications on levodopa treatment in Parkinson's disease

“…Another study in 31 patients being treated with oral levodopa found that peak-time gastric emptying (T max ) > 60 min was more common in patients with plasma levodopa peak at 2 h (69%) than in patients with plasma levodopa peak at 1 h (22%; P < 0.05), thus illustrating that DGE may be correlated with delayed ON-time [74]. However, other studies report more equivocal findings indicating that DGE is one of multiple factors that may affect oral levodopa pharmacokinetics, including PD stage, influence of levodopa itself on gastric function/ emptying, and timing of levodopa administration (ie, during ON or OFF periods) [31,[75][76][77]. Nonetheless, DGE is believed to be a key risk factor for motor fluctuations [30,70].…”