Abstract
Food-drug interaction is an infrequently considered aspect in clinical practice. Usually, drugs are taken together with meals and what follows may adversely affect pharmacokinetic and pharmacodynamic properties, and hence, the therapeutic effects. In this study, a computational protocol was proposed to explain the different assimilations of two µ-receptors agonists, eluxadoline and loperamide, with a peculiar pharmacokinetic profile. Compared to loperamide, eluxadoline is absorbed less after the intake of a fatty meal, and the LogP values do not explain this event. Firstly, keeping in mind the different pH in the intestinal tract, the protonation states of both compounds were calculated. Then, all structures were subjected to a conformational search by using MonteCarlo and Molecular Dynamics methods, with solvation terms mimicking the water and weak polar solvent (octanol). Both computational results showed that eluxadoline has less conformational freedom in octanol, unlike loperamide, which exhibits constant behavior in both solvents. Therefore, we hypothesize that fatty meal causes the “closure” of the eluxadoline molecule to prevent the exposure of the polar groups and their interaction with water, necessary for the drug absorption. Based on our results, this work could be a reasonable “case study”, useful for future investigation of the drug pharmacokinetic profile.
Highlights
Food-drug interactions often cause alterations of the pharmacokinetics or pharmacodynamics of a drug or nutritional element [1]
An example is the case of eluxadoline (Viberzi), a new medication approved by the Food and Drug Administration (FDA) for the treatment of adults with irritable bowel syndrome (IBS) with diarrhea [4]
The global minima will be mentioned taking into account the name of the compound, the conformational technique (Monte Carlo, MC, or Molecular Dynamics, MD), the energy rank (1,2, etc.) and the solvent
Summary
Food-drug interactions often cause alterations of the pharmacokinetics or pharmacodynamics of a drug or nutritional element [1]. An example is the case of eluxadoline (Viberzi), a new medication approved by the Food and Drug Administration (FDA) for the treatment of adults with irritable bowel syndrome (IBS) with diarrhea [4]. Eluxadoline has been reported to be effective and safe in treating both altered bowel habit and pain in IBS-D patients [10]. Computational techniques represent powerful tools in the pharmaceutical industry and academia [18,19] They are widely applied to drug discovery in different applications fields, but they are useful for the deep comprehension of the ligand selectivity and the targets folding [20,21,22,23,24,25,26,27,28,29,30,31,32]. The global minima will be mentioned taking into account the name of the compound (loperamide, L, or eluxadoline, E1, E2 and E3), the conformational technique (Monte Carlo, MC, or Molecular Dynamics, MD), the energy rank (1,2, etc.) and the solvent (water, w, or octanol, o)
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