To restrict or not to restrict? Practical considerations for optimizing dietary protein interactions on levodopa absorption in Parkinson's disease

Abstract

Administration of levodopa for Parkinson's disease (PD) has remained the most effective therapy for symptom management despite being in use for over 50 years. Advancing disease and age, changing tolerability and gastrointestinal (GI) dysfunction may result in change in dietary habits and body weight, as well as unpredictable motor fluctuations and dyskinesias. Dietary proteins which convert into amino acids after digestion are implicated as major factors that inhibit levodopa absorption. For people living with PD (PwP) who experience motor fluctuations, low protein diets (LPD) and protein redistribution diets (PRD) may be effective and are often recommended as a non-pharmacologic approach for improving levodopa bioavailability. However, there is a lack of consensus on a standard definition of these diets and appropriate treatment algorithms for usage. This may be due to the paucity of high-level evidence of LPD and PRD in PwP and whether all or specific subgroups of patients would benefit from these strategies. Managing diet and protein intake with proper education and monitoring may reduce complications associated with these diets such as dyskinesias and unintentional weight loss. Additionally, alterations to medications and GI function may alter levodopa pharmacokinetics. In this narrative review we focus on 1) mechanisms of dietary protein and levodopa absorption in the intestine and blood brain barrier, 2) dietetic approaches to manage protein and levodopa interactions and 3) practical issues for treating PwP as well as future directions to be considered.

Fig. 1. Transport of levodopa and free amino acids across the intestine, blood, and brain.

Dietary proteins are broken down to free amino acids (yellow circles and squares) may compete with levodopa absorption. a When taken with meals, levodopa is competitively inhibited by neutral and cationic amino acids for uptake by b^0,+AT-rBAT (SLC7A9-SLC3A1) decreasing transport across enterocytes by LAT2-4F2hc (SLC7A8-SLC3A2). After entering systemic circulation, transport across endothelial cells of the BBB by LAT1-4F2hc (SLC7A5-SLC3A2) may be reduced due to amino acid competition. b When taken on an empty stomach, levodopa is transported by b⁰,+AT-rBAT (SLC7A9-SLC3A1) and exits the basolateral side primarily by TAT1 (SLC16A10) and LAT2-4F2hc (SLC7A8-SLC3A2). Levodopa enters systemic circulation and transported across the BBB by LAT1-4F2hc (SLC7A5-SLC3A2) where it is metabolized into dopamine or 3-OMD. c Early peripheral metabolism of levodopa is prevented by co-administration of AADC and/or COMT inhibitors. L-DOPA, levodopa; AADC, aromatic L-amino acid decarboxylase; COMT, catecholamine-O-methyltransferase; 3-OMD, 3-O-methyldopa; SLC, solute carrier family; BBB, blood brain barrier.

Fig. 2. Factors that influence pharmacokinetics and response of levodopa.

IR Immediate-release, CR Continuous-release, ER Extended-release, SIBO Small intestine bacterial overgrowth, H.pylori Helicobacter pylori, BMI Body mass index.