Irregular gastrointestinal drug absorption in Parkinson's disease.
ABSTRACT Symptomatic treatment of Parkinson's disease (PD) is based on the dopamine precursor levodopa. Levodopa is only absorbed in the small intestine, where transit time is approximately 3 h and the plasma elimination half-life is short. Therefore, gastric emptying is a major determining factor for onset of symptom relief.
Gastric emptying is delayed in PD, thereby causing motor fluctuations such as 'delayed on'. Factors that further slow gastric emptying should be recognised and eliminated if possible.
A literature search was performed with the aim to cover the area of irregular gastrointestinal drug absorption in PD.
Methods for facilitation of pyloric passage or increase of bioavailability are discussed. Development of new drug formulations and alternative routes of administration is ongoing. Transdermal patches and pumps for subcutaneous or intraduodenal infusions are available for patients with severe fluctuations due to erratic gastric emptying.
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ABSTRACT: Although many surgical procedures originally associated with gastroparesis are less commonly performed nowadays, several more recently developed upper abdominal procedures may be complicated by the development of gastroparesis. Gastroparesis has been described in association with neurologic disorders ranging from Parkinson disease to muscular dystrophy, and its presence may have important implications for patient management and prognosis. Although scleroderma is most frequently linked with gastrointestinal motility disorder, gastroparesis has been linked to several other connective tissue disorders. The management of these patients presents several challenges, and is best conducted in the context of a dedicated and skilled multidisciplinary team. Copyright © 2015 Elsevier Inc. All rights reserved.
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ABSTRACT: Levodopa (L-DOPA) is the naturally occurring precursor amino acid for dopamine and the main therapeutic agent for neurologic disorders due to dopamine depletion, such as Parkinson's disease. Levodopa absorption in small intestine has been suggested to be mediated by the large neutral amino acids transport machinery, but the identity of the involved transporters is unknown. Clinically, co-administration of levodopa and dietary amino acids is avoided to decrease competition for transport in intestine and at the blood brain barrier. Levodopa is routinely co-administered with levodopa metabolism inhibitors (dopa decarboxylase and cathechol-o-methyl transferase inhibitors) that share structural similarity with levodopa. In this systematic study involving Xenopus laevis oocytes and MDCK epithelia expression systems and ex vivo preparations from wild type and knockout mice, we identified the neutral and dibasic amino acids exchanger (antiporter) b(0,+)AT-rBAT (SLC7A9-SLC3A1) as the luminal intestinal levodopa transporter. The major luminal co-transporter (symporter) B0AT1 (SLC6A19) was not involved in levodopa transport. L-leucine and L-arginine competed with levodopa across the luminal enterocyte membrane as expected for b(0,+)AT-rBAT substrates whereas dopa decarboxylase and cathechol-o-methyl transferase inhibitors had no effect. The presence of amino acids in the basolateral compartment mimicking the postprandial phase increased transepithelial levodopa transport by stimulating basolateral efflux via the antiporter LAT2-4F2 (SLC7A8-SLC3A2). Additionally, the aromatic amino acid uniporter TAT1 (SLC16A10) was shown to play a major role in levodopa efflux from intestinal enterocytes. These results identify the molecular mechanisms mediating small intestinal levodopa absorption and suggest strategies for optimization of delivery and absorption of this important pro-drug.Journal of Pharmacology and Experimental Therapeutics 07/2014; 351(1). DOI:10.1124/jpet.114.216317 · 3.86 Impact Factor