Irregular gastrointestinal drug absorption in Parkinson's disease
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.
Available from: Tamara Ramadan
- "Since its introduction in 1968, levodopa (L-dihydroxyphenylalanine , L-DOPA) is the major therapeutic agent in treating PD (Poewe et al., 2010). After passing the blood-brain barrier (BBB), levodopa is converted into dopamine by the dopadecarbocylase (DDC) (Nyholm and Lennernas, 2008). To prevent levodopa metabolism prior to its transport across the BBB, orally administered levodopa is given in combination with a DDC inhibitor (e.g., carbidopa or benserazide) (Hollingworth et al., 2011). "
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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.
Available from: Paul M. Gallo
- "The time since the last dose of medication was recorded and consistent across laboratory visits. Due to the wide variability in the absorption of medications  we believe this approach was more effective in identifying peak effect. The treadmill was calibrated per the manufacturer's recommendations. "
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ABSTRACT: Background: Gait impairment is common in Parkinson's disease (PD) and may result in greater energy expenditure, poorer walking economy, and fatigue during activities of daily living. Auditory cueing is an effective technique to improve gait; but the effects on energy expenditure are unknown. Objective: To determine whether energy expenditure differs in individuals with PD compared with healthy controls and if auditory cueing improves walking economy in PD. Methods: Twenty participants (10 PD and 10 controls) came to the laboratory for three sessions. Participants performed two, 6-minute bouts of treadmill walking at two speeds (1.12 m·sec-1 and 0.67 m·sec-1). One session used cueing and the other without cueing. A metabolic cart measured energy expenditure and walking economy was calculated (energy expenditure/power). Results: PD had worse walking economy and higher energy expenditure than control participants during cued and non-cued walking at the 0.67 m·sec-1 speed and during non-cued walking at the 1.12 m·sec-1. With auditory cueing, energy expenditure and walking economy worsened in both participant groups. Conclusions: People with PD use more energy and have worse walking economy than adults without PD. Walking economy declines further with auditory cuing in persons with PD.
Available from: Teruo Murakami
- "*: P < 0.05 initiation of digestion, holding and crushing of ingested food, gastric motility and gastric emptying rate (GER) is modulated under various diseased states (Pohle and Domschke 2003; Hardoff et al. 2001; Castell et al. 2004). For example, in patients with Parkinson's disease, the GER is delayed compared with control healthy volunteers (Hardoff et al. 2001; Nyholm and Lennernäs 2008), and some patients with Parkinson's disease develop response fluctuations due to a significant delay in GER after several years of chronic treatment with levodopa (Djaldetti et al. 1996; Hardoff et al. 2001). "
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ABSTRACT: Influx or efflux transporter(s), or both, are frequently involved in the intestinal absorption of various therapeutic drugs. In the present study, the effects of altered gastric emptying rates (GER) on intestinal absorption of quinidine (a substrate for P-glycoprotein, P-gp) and methotrexate (a substrate for multiple-transporters including proton-coupled folate transporter, PCFT) were examined to find their main absorption sites along the intestine employing rats. In untreated control rats, quinidine administered orally was rapidly absorbed from the proximal intestine, where P-gp is less expressed. Increased GER, which transferred an unabsorbable model compound to the middle intestine within 15 min after oral administration, exerted no significant effects on the extent of oral bioavailability of quinidine, whereas it increased the initial absorption rate greatly. Decreased GER, in which more than 50% of a model compound administered was retained in the stomach even 1 h after administration, decreased the onset time of intestinal absorption, but not the extent of oral bioavailability of quinidine. In untreated control rats, methotrexate was absorbed efficiently from the proximal intestine under acidic conditions, where PCFT is abundantly expressed. Increased GER significantly decreased, and decreased GER slightly increased the oral bioavailability of methotrexate. In conclusion, altered GER was found to affect the transporter-mediated intestinal absorption of drugs in different manners, depending on the solubility, membrane permeability, luminal concentration of the drug, luminal pH, substrate specificity, and the expression sites of transporter.
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