The Molecular Mechanism of Intestinal Levodopa Absorption and Its Possible Implications for the Treatment of Parkinson’s Disease

Camargo, Simone M. R.; Vuille‐dit‐Bille, Raphael N.; Mariotta, Luca; Ramadan, Tamara; Huggel, Katja; Singer, Dustin; Götze, Oliver; Verrey, François

doi:10.1124/jpet.114.216317

Cited by 68 publications

(66 citation statements)

References 59 publications

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“…Levodopa is used in the management of Parkinson's disease. Its absorption from the small intestine is mediated through an unknown large neutral amino acids transport pump (Carmago et al, 2014). The coadministration of Levodopa with dietary amino acids causes an increase in the competition for transport in the small intestine and at the blood-brain barrier, thus decreasing the bioavailability of Levodopa (Carmago et.…”

Section: Discussionmentioning

confidence: 99%

Knowledge of Food and Drug Interactions among Nurses: Assessment Strategy for Continuing Education

Enwerem¹,

Okunji²

2016

IJHE

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The effect of medication errors on patient quality care and safety is a critical ongoing concern requiring solutions. Although medication safety has been a concern of all healthcare professions, registered nurses play an important role in medication safety as patients' advocates. A cross sectional study with structured questionnaire on common FDI found in the medical journal was used in this study. The questionnaire consisted of 37 questions (dichotomous and multiple choice questions). A convenience sample of 271 nurses from different inpatient community nursing units (60 medical surgical, 60 telemetry, 29 Intensive care (ICU), 21 emergency, and 101 'others') across the DC-MD-VA metropolitan areas were recruited for this study. The data was subjected to descriptive analysis. The study protocol was approved by the Office of Regulatory, Research Compliance, Howard University. The result, showed no significant differences in the knowledge of FDI among the 5 groups of registered nurses. The authors propose continuing education for all nurses to update dosage calculation, follow drug administration protocol and enhance knowledge of pharmacology as avenues to reduce medication error. The authors also recommend that future studies focus on a larger sample size, inclusion of more associated FDI variables and use of high level statistical analysis.

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Section: Discussionmentioning

confidence: 99%

Knowledge of Food and Drug Interactions among Nurses: Assessment Strategy for Continuing Education

Enwerem¹,

Okunji²

2016

IJHE

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“…9 The latter finding provides opportunities for augmenting dietary intervention. Serine supplementation increased in silico the bioavailability of levodopa for PD patients with moderately impaired GER (Figure 3d).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that, in addition to luminal competition, the presence of amino acids in the basolateral side of enterocytes trans-stimulates the absorption of levodopa leading to a higher bioavailability of the drug. 9 …”

Section: Introductionmentioning

confidence: 99%

Model-based dietary optimization for late-stage, levodopa-treated, Parkinson’s disease patients

Guebila

Thiele

2016

npj Syst Biol Appl

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Levodopa has been the gold standard for Parkinson’s disease treatment for more than 40 years. Its bioavailability is hindered by dietary amino acids, leading to fluctuations in the motor response particularly in late-stage (stage 3 and 4 on Hoehn and Yahr scale) patients. The routine dietary intervention consists of low-protein (<0.8 g/kg) diets or the redistribution of daily protein allowance to the last meal. Computational modeling was used to examine the fluctuation of gastrointestinal levodopa absorption under consideration of the diet by (i) identifying the group of patients that could benefit from dietary interventions, (ii) comparing existing diet recommendations for their impact on levodopa bioavailability, and (iii) suggesting a mechanism-based dietary intervention. We developed a multiscale computational model consisting of an ordinary differential equations-based advanced compartmentalized absorption and transit (ACAT) gut model and metabolic genome-scale small intestine epithelial cell model. We used this model to investigate complex spatiotemporal relationship between dietary amino acids and levodopa absorption. Our model predicted an improvement in bioavailability, as reflected by blood concentrations of levodopa with protein redistribution diet by 34% compared with a low-protein diet and by 11% compared with the ante cibum (a.c.) administration. These results are consistent with the reported better outcome in late-stage patients. A systematic analysis of the effect of different amino acids in the diet suggested that a serine-rich diet could improve the bioavailability by 22% compared with the a.c. administration. In addition, the slower gastric emptying rate in PD patients exacerbates the loss of levodopa due to competition. Optimizing dietary recommendations in quantity, composition, and intake time holds the promise to improve levodopa efficiency and patient’s quality of life based on highly detailed, mechanistic models of gut physiology endowed with improved extrapolative properties, thus paving the way for precision medical treatment.

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“…Some AA, peptide, and other SLC transporters have been shown to carry a broad variety of drugs (e.g., levodopa, antibiotics, ACE inhibitors etc)45. Thus, our approach could potentially be helpful in modeling SLC transporter responses to drugs even when the protein expression of candidate transporters is not known.…”

Section: Discussionmentioning

confidence: 99%

Quantifying the relative contributions of different solute carriers to aggregate substrate transport

Taslimifar

Oparija

Verrey

et al. 2017

Sci Rep

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Determining the contributions of different transporter species to overall cellular transport is fundamental for understanding the physiological regulation of solutes. We calculated the relative activities of Solute Carrier (SLC) transporters using the Michaelis-Menten equation and global fitting to estimate the normalized maximum transport rate for each transporter (Vmax). Data input were the normalized measured uptake of the essential neutral amino acid (AA) L-leucine (Leu) from concentration-dependence assays performed using Xenopus laevis oocytes. Our methodology was verified by calculating Leu and L-phenylalanine (Phe) data in the presence of competitive substrates and/or inhibitors. Among 9 potentially expressed endogenous X. laevis oocyte Leu transporter species, activities of only the uniporters SLC43A2/LAT4 (and/or SLC43A1/LAT3) and the sodium symporter SLC6A19/B0AT1 were required to account for total uptake. Furthermore, Leu and Phe uptake by heterologously expressed human SLC6A14/ATB0,+ and SLC43A2/LAT4 was accurately calculated. This versatile systems biology approach is useful for analyses where the kinetics of each active protein species can be represented by the Hill equation. Furthermore, its applicable even in the absence of protein expression data. It could potentially be applied, for example, to quantify drug transporter activities in target cells to improve specificity.

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The Molecular Mechanism of Intestinal Levodopa Absorption and Its Possible Implications for the Treatment of Parkinson’s Disease

Cited by 68 publications

References 59 publications

Knowledge of Food and Drug Interactions among Nurses: Assessment Strategy for Continuing Education

Knowledge of Food and Drug Interactions among Nurses: Assessment Strategy for Continuing Education

Model-based dietary optimization for late-stage, levodopa-treated, Parkinson’s disease patients

Quantifying the relative contributions of different solute carriers to aggregate substrate transport

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