Drug Permeability and Metabolism in the Gut

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Pharmacology and Drug Metabolism".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 2470

Special Issue Editor


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Guest Editor
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Interests: PK/PD; drug development; translational biopharmaceutics; oral drug absorption; intestinal permeability; drug targeting; prodrugs; PBPK modeling; autoimmune disorders; IBD; neurodegenerative disorders; neuroimmune pharmacology
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Special Issue Information

Dear Colleagues,

The gut is the key organ for the absorption of water and nutrients as well as for drug metabolism and absorption. The gut consists of several regions, including the stomach, the small intestine (encompasing duodenum, jejunum, and ileum), and the large intestine. The microenvironment in these regions and even conditions within each region itself rely largely on parameters such as the luminal pH, mucus properties, fluid composition, tight junctions, different intestinal morphologies throughout the gut, microbiota, and many others; it is also well known that there are clear differences in the expression profile of drug transporters and metabolising enzymes along the intestinal tract. All of these, alone or in combination, influence the fate of the drug following oral administration and lead to variable drug absorption, pharmacokinetic (PK) and consequently pharmacodynamic (PD) profiles.

Intestinal permeability is a crucial factor for orally administered drugs, and can in some cases be assisted by uptake transporters or limited by efflux transporters and metabolic enzymes in the gut. It is crucial to identify gut enzymes that induce the biotransformation of orally administered drug molecules as well as intestinal transporters and their pharmacokinetic, pathophysiological, and pharmacogenetic roles in drug transport. Besides scenarios where regional-dependent intestinal permeability occurs, lately, regional differences in human intestinal drug metabolism have been identified as well. Aside from the gut microevironment, these processes are often influenced by the food intake as well as the subject’s age, race, disease status, and BMI.  While drug metabolism in the liver has been widely researched, the pharmaceutical research has further to go in terms of adopting a standardised approach for the characterisation and quantitative prediction of intestinal metabolism. In terms of the development of oral drug candidates, a detailed assessment of intestinal metabolism in the context of typical DMPK activities within the drug-discovery programmes all the way to candidate drug nomination is needed. In this Special Issue, work which focuses on intestinal drug permeability as well as intestinal metabolism is of great interest. Authors are welcome to contribute both original research and review articles.

Dr. Milica Markovic
Guest Editor

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Published Papers (1 paper)

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Research

23 pages, 811 KiB  
Article
Effects of a Metabolic Mixture on Gut Inflammation and Permeability in Elderly Patients with Chronic Kidney Disease: A Proof-of-Concept Study
by Roberto Aquilani, Piergiorgio Bolasco, Stefano Murtas, Roberto Maestri, Paolo Iadarola, Cristian Testa, Maria Luisa Deiana, Maria Paola Esposito, Rita Contu, Mariella Cadeddu, Romina Secci and Federica Boschi
Metabolites 2022, 12(10), 987; https://doi.org/10.3390/metabo12100987 - 18 Oct 2022
Cited by 3 | Viewed by 1777
Abstract
Intestinal barrier dysfunction is a risk factor for the progression of Chronic Kidney Disease (CKD). In this proof-of-concept study, we tested the effects of a mixture of Essential Amino Acids (EAAs) and mitochondrial substrates on intestinal inflammation and permeability of CKD patients. Eight [...] Read more.
Intestinal barrier dysfunction is a risk factor for the progression of Chronic Kidney Disease (CKD). In this proof-of-concept study, we tested the effects of a mixture of Essential Amino Acids (EAAs) and mitochondrial substrates on intestinal inflammation and permeability of CKD patients. Eight patients with stage 3b-4 CKD and 11 healthy controls after overnight fasting underwent fecal measures of calprotectin and zonulin levels (indicators of gut inflammation and permeability, respectively) and determinations of plasma amino acids. Only CKD patients were supplemented with the mixture (8 g/d diluted in water). Compared to controls, baseline fecal calprotectin, zonulin and plasma levels of some AA in CKD patients were significantly higher (p = 0.005; p = 0.001 and p = 0.02 to 0.003, respectively). After six months of supplementation, CKD baseline fecal levels of calprotectin and zonulin significantly (borderline for zonulin) decreased (p = 0.008 and p = 0.05, respectively). Plasma AA concentrations, including glutamine and alanine, were higher than at the baseline (p: 0.05 to 0.008). The supplementation of this mixture was associated with improved intestinal barrier dysfunction. Increased plasma AA levels might contribute to the improvement of gut barrier dysfunction. Full article
(This article belongs to the Special Issue Drug Permeability and Metabolism in the Gut)
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