TY - JOUR
T1 - In Silico Food-Drug Interaction
T2 - A Case Study of Eluxadoline and Fatty Meal
AU - Maruca, A.
AU - Lupia, A.
AU - Rocca, R.
AU - Keszthelyi, D.
AU - Corsetti, M.
AU - Alcaro, S.
N1 - Funding Information:
Funding: A.M. was supported by the Ministero dell’Istruzione e dell’Università e della Ricerca MIUR research project “NUTRAMED PON 03PE000_78_2”.
Funding Information:
Acknowledgments: This article is based upon work from COST Action UNGAP (CA16205), supported by COST (European Cooperation in Science and Technology).
Funding Information:
A.M. was supported by the Ministero dell?Istruzione e dell?Universit? e della Ricerca MIUR research project ?NUTRAMED PON 03PE000_78_2?. This article is based upon work from COST Action UNGAP (CA16205), supported by COST (European Cooperation in Science and Technology).
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
KW - conformational analysis
KW - eluxadoline
KW - food-drugs interactions
KW - loperamide
KW - molecular dynamics
KW - BINDERS
KW - 1ST
KW - FORCE-FIELD
KW - MUDELTA
KW - IBS
KW - DERIVATIVES
KW - IRRITABLE-BOWEL-SYNDROME
U2 - 10.3390/ijms21239127
DO - 10.3390/ijms21239127
M3 - Article
C2 - 33266221
SN - 1661-6596
VL - 21
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 23
M1 - 9127
ER -