Gastrointestinal barriers to levodopa transport and absorption in Parkinson's disease

Abstract

Levodopa is the gold standard for the symptomatic treatment of Parkinson's disease (PD). There are well documented motor and non‐motor fluctuations, however, that occur almost inevitably once levodopa is started after a variable period in people with PD. Whilst brain neurodegenerative processes play a part in the pathogenesis of these fluctuations, a range of barriers across the gastrointestinal (GI) tract can alter levodopa pharmacokinetics, ultimately contributing to non‐optimal levodopa response and symptoms fluctuations. GI barriers to levodopa transport and absorption include dysphagia, delayed gastric emptying, constipation, Helicobacter pylori infection, small intestinal bacterial overgrowth and gut dysbiosis. In addition, a protein‐rich diet and concomitant medication intake can further alter levodopa pharmacokinetics. This can result in unpredictable or sub‐optimal levodopa response, ‘delayed on’ or ‘no on’ phenomena. In this narrative review, we provided an overview on the plethora of GI obstacles to levodopa transport and absorption in PD and their implications on levodopa pharmacokinetics and development of motor fluctuations. In addition, management strategies to address GI dysfunction in PD are highlighted, including use of non‐oral therapies to bypass the GI tract.

Management of Gastrointestinal Symptoms in Parkinson’s Disease

“…Approximately 1 in 4 patients with PD suffer from bloating, and bloating is the GI symptom most associated with referral to a GI specialist for management in this population 15 . In addition to being difficult to treat, this is perhaps driven by a common concern among neurologists treating patients with PD that bloating, as a reflection of an underlying motility disorder, contributes to motor fluctuations, a phenomenon in which patients with PD on levodopa therapy experience a decline in the usual benefit from a dose of the medication 62 …”

Can Continuous Levodopa Delivery Be Achieved in the Absence of Intrajejunal Levodopa Infusion? Implications for India and Underserved Countries

“…Following the use of optimization of levodopa therapy through enzyme inhibition and long‐acting dopamine agonists to address the problems of pulsatile therapies in PD, several device‐aided therapy options have been developed to provide, at least in part, CDD to patients with motor complications. The mechanisms appear to be linked to the concept of bypassing the gastrointestinal (GI) barriers to oral absorption and transport of levodopa 11 . Subcutaneous apomorphine infusion, 12,13 for example, has been classified in the United Kingdom (UK) as medical therapy able to provide CDS to tackle fluctuations and dyskinesias.…”

“…Levodopa is characterized by limited oral bioavailability and extremely short half‐life, therefore, representing one of the most difficult molecules to control pharmacologically 11 . Part of its limited bioavailability, as previously discussed, lies in the numerous metabolic pathways and enzymatic degradations encountered across its journey from the GI tract to the brain, beyond the blood–brain barrier.…”

“…Barriers to absorption are represented by the action of human and bacterial decarboxylases, 44,45 the saturable facilitated transport system, where levodopa competes with other dietary amino acids, 46 the peripheral COMT action, and small intestinal bacterial overgrowth 47 . In addition, Helicobacter pylori ( H. pylori ) infection may impair levodopa absorption by various mechanisms, although the role of its eradication in improving the motor effect of oral levodopa is disputed, there being evidence both for and against 11,48 . GI barriers to levodopa transport include dysphagia, esophageal alterations, delayed gastric emptying, 49 slow transit, and outlet constipation 11 .…”

“…GI dysfunction, in addition, is a cardinal non‐motor symptom 42 and a feature of the recently described noradrenergic subtype of PD, 43 which adds to the overall challenge of levodopa absorption when administered orally, due to both absorption as well as transport barriers. Addressing these obstacles with relatively cheap lifestyle‐ and diet‐based advice would, therefore, result in better bioavailability of oral levodopa and, subsequently, in a less discontinuous dopaminergic stimulation 11 . Barriers to absorption are represented by the action of human and bacterial decarboxylases, 44,45 the saturable facilitated transport system, where levodopa competes with other dietary amino acids, 46 the peripheral COMT action, and small intestinal bacterial overgrowth 47 .…”