Intestinal Drug Absorption

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biopharmaceutics".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 37399

Special Issue Editors


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Guest Editor
1. Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
2. Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
Interests: pharmacology; Alzheimer’s disease; depression; epilepsy; pharmacokinetics; intranasal administration; nose-to-brain
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CICS-UBI—Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
Interests: pharmacokinetics; ADME; bioavailability; drug evaluation; drug delivery; systemic drug exposure
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

In spite of the recent advances in alternative routes of drug delivery, oral drug administration remains the method of choice for the treatment of numerous diseases. Nevertheless, various factors contribute to the low intestinal absorption and bioavailability of orally administered drugs, namely, drug- and formulation-related parameters, such as drug solubility and permeability, drug product dissolution, and gastrointestinal conditions including transit time and gut wall conditions relevant to metabolism, passive diffusion, and active transport of drugs. In this context, intestinal and hepatic pre-systemic metabolism is mediated by cytochrome P450 enzymes together with the ATP-binding cassette transporter superfamily consisting of P-glycoprotein, multidrug resistant proteins, and breast cancer resistance proteins; these factors are considered to be the major determinants of oral drug bioavailability.

Several strategies have been developed and exploited to overcome the solubility and permeability issues associated with drugs that have oral bioavailability problems. While some common approaches combine enzymatic inhibitors with absorption modification excipients or chemical permeation enhancers, others focus on developing lipid nanoparticle multisystems. The implementation of in vitro and in silico predictive tools, followed by in vivo evaluation, is thus mandatory for increasing the success of drug discovery and development programs.

This Special Issue aims to address the obstacles of intestinal drug absorption, novel strategies that are under current investigation, and the efforts that are being made to develop biorelevant methodologies to accurately predict oral drug absorption.

Dr. Gilberto Alves
Dr. Ana Fortuna
Guest Editors

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Keywords

  • intestinal permeability
  • absorption
  • bioavailability
  • ABC efflux transporters
  • P-glycoprotein
  • intestinal models
  • oral delivery
  • permeation enhancers

Published Papers (8 papers)

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Research

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16 pages, 4430 KiB  
Article
Mucin-Protected Caco-2 Assay to Study Drug Permeation in the Presence of Complex Biorelevant Media
by Dong Ye, Álvaro López Mármol, Verena Lenz, Patricia Muschong, Anita Wilhelm-Alkubaisi, Manuel Weinheimer, Mirko Koziolek, Kerstin A. Sauer, Loic Laplanche and Mario Mezler
Pharmaceutics 2022, 14(4), 699; https://doi.org/10.3390/pharmaceutics14040699 - 24 Mar 2022
Cited by 7 | Viewed by 3213
Abstract
The poor solubility and permeability of compounds beyond Lipinski’s Rule of Five (bRo5) are major challenges for cell-based permeability assays. Due to their incompatibility with gastrointestinal components in biorelevant media, the exploration of important questions addressing food effects is limited. Thus, we established [...] Read more.
The poor solubility and permeability of compounds beyond Lipinski’s Rule of Five (bRo5) are major challenges for cell-based permeability assays. Due to their incompatibility with gastrointestinal components in biorelevant media, the exploration of important questions addressing food effects is limited. Thus, we established a robust mucin-protected Caco-2 assay to allow the assessment of drug permeation in complex biorelevant media. To do that, the assay conditions were first optimized with dependence of the concentration of porcine mucin added to the cells. Mucin-specific effects on drug permeability were evaluated by analyzing cell permeability values for 15 reference drugs (BCS class I–IV). Secondly, a sigmoidal relationship between mucin-dependent permeability and fraction absorbed in human (fa) was established. A case study with venetoclax (BCS class IV) was performed to investigate the impact of medium complexity and the prandial state on drug permeation. Luminal fluids obtained from the tiny-TIM system showed a higher solubilization capacity for venetoclax, and a better read-out for the drug permeability, as compared to FaSSIF or FeSSIF media. In conclusion, the mucin-protected Caco-2 assay combined with biorelevant media improves the mechanistic understanding of drug permeation and addresses complex biopharmaceutical questions, such as food effects on oral drug absorption. Full article
(This article belongs to the Special Issue Intestinal Drug Absorption)
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18 pages, 2097 KiB  
Article
Transport Mechanisms of Polymannuronic Acid and Polyguluronic Acid Across Caco-2 Cell Monolayers
by Yu Wang, Xu Bai, Bo Hu, Maochen Xing, Qi Cao, Aiguo Ji and Shuliang Song
Pharmaceutics 2020, 12(2), 167; https://doi.org/10.3390/pharmaceutics12020167 - 17 Feb 2020
Cited by 17 | Viewed by 3281
Abstract
Detailed knowledge of the intestinal transport of polymannuronic acid (PM) and polyguluronic acid (PG) is critical for understanding their biological activities. To investigate the transport in the gastrointestinal tract, PM and PG were chemically modified with tyramine and conjugated with fluorescein isothiocyanate (FITC) [...] Read more.
Detailed knowledge of the intestinal transport of polymannuronic acid (PM) and polyguluronic acid (PG) is critical for understanding their biological activities. To investigate the transport in the gastrointestinal tract, PM and PG were chemically modified with tyramine and conjugated with fluorescein isothiocyanate (FITC) to synthesize FITC-PM (F-PM) and FITC-PG (F-PG) successfully. The transport mechanisms of F-PM and F-PG across the intestinal epithelial cell monolayers (Caco-2 cell monolayers) were then investigated. The results demonstrated that the transport of F-PM and F-PG into epithelial cells was time- and energy-dependent, which was mediated by the macropinocytosis pathway and the clathrin- and caveolae (or lipid raft)-mediated endocytic pathway. The transport process of F-PM and F-PG in Caco-2 cells depended on the acidification of endosomes and involved lysosomes. Tubulin mediated the transport of F-PM, but not of F-PG. Moreover, the absorption enhancer chitosan (CS) promoted the transport of F-PM and F-PG, increasing the apparent permeability coefficient (Papp) by 1.9-fold and 2.6-fold, respectively, by reversibly opening the tight junction (TJ). In summary, this study provided a comprehensive understanding of the transport of PM and PG in the small intestinal epithelial cells, which will provide a theoretical basis for the development of PM and PG with good intestinal absorption. Full article
(This article belongs to the Special Issue Intestinal Drug Absorption)
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14 pages, 1729 KiB  
Article
Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats
by Anallely López-Yerena, Anna Vallverdú-Queralt, Raf Mols, Patrick Augustijns, Rosa M. Lamuela-Raventós and Elvira Escribano-Ferrer
Pharmaceutics 2020, 12(2), 134; https://doi.org/10.3390/pharmaceutics12020134 - 5 Feb 2020
Cited by 22 | Viewed by 3074 | Correction
Abstract
Oleocanthal (OLC), a phenolic compound of extra virgin olive oil (EVOO), has emerged as a potential therapeutic agent against a variety of diseases due to its anti-inflammatory activity. The aim of the present study is to explore its in vivo intestinal absorption and [...] Read more.
Oleocanthal (OLC), a phenolic compound of extra virgin olive oil (EVOO), has emerged as a potential therapeutic agent against a variety of diseases due to its anti-inflammatory activity. The aim of the present study is to explore its in vivo intestinal absorption and metabolism. An in situ perfusion technique in rats was used, involving simultaneous sampling from the luminal perfusate and mesenteric blood. Samples were analysed by UHPLC–MS–MS for the presence of oleocanthal (OLC) and its metabolites. OLC was mostly metabolized by phase I metabolism, undergoing hydration, hydrogenation and hydroxylation. Phase II reactions (glucuronidation of hydrogenated OLC and hydrated metabolites) were observed in plasma samples. OLC was poorly absorbed in the intestine, as indicated by the low effective permeability coefficient (2.23 ± 3.16 × 10−5 cm/s) and apparent permeability coefficient (4.12 ± 2.33 × 10−6 cm/s) obtained relative to the values of the highly permeable reference compound levofloxacin (LEV). The extent of OLC absorption reflected by the area under the mesenteric blood-time curve normalized by the inlet concentration (AUC) was also lower than that of LEV (0.25 ± 0.04 vs. 0.64 ± 0.03, respectively). These results, together with the observed intestinal metabolism, suggest that OLC has a moderate-to-low oral absorption; but higher levels of OLC are expected to reach human plasma vs. rat plasma. Full article
(This article belongs to the Special Issue Intestinal Drug Absorption)
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Review

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17 pages, 649 KiB  
Review
The Role of Functional Excipients in Solid Oral Dosage Forms to Overcome Poor Drug Dissolution and Bioavailability
by Jannes van der Merwe, Jan Steenekamp, Dewald Steyn and Josias Hamman
Pharmaceutics 2020, 12(5), 393; https://doi.org/10.3390/pharmaceutics12050393 - 25 Apr 2020
Cited by 83 | Viewed by 14673
Abstract
Many active pharmaceutical ingredients (APIs) exhibit poor solubility and low dissolution rates in aqueous environments such as the luminal fluids of the gastrointestinal tract. The oral bioavailability of these compounds is usually very low as a result of their poor solubility properties. In [...] Read more.
Many active pharmaceutical ingredients (APIs) exhibit poor solubility and low dissolution rates in aqueous environments such as the luminal fluids of the gastrointestinal tract. The oral bioavailability of these compounds is usually very low as a result of their poor solubility properties. In order to improve the bioavailability of these poorly soluble drugs, formulation strategies have been applied as a means to improve their aqueous solubility and dissolution rates. With respect to formulation approaches, excipients can be incorporated in the formulation to assist in the dissolution process of the drug, or specialized dosage forms can be formulated that improve dissolution rate through various mechanisms. This paper provides an overview of selected excipients (e.g., alkalinizing agents, surfactants and sugars) that can be used in formulations to increase the dissolution rate as well as specialized dosage forms such as self-emulsifying delivery systems and formulation techniques such as inclusion complexes and solid dispersions. These formulation approaches are discussed with available examples with specific reference to positive outcomes in terms of drug solubility and bioavailability enhancement. Full article
(This article belongs to the Special Issue Intestinal Drug Absorption)
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19 pages, 932 KiB  
Review
Synergistic Mechanisms of Constituents in Herbal Extracts during Intestinal Absorption: Focus on Natural Occurring Nanoparticles
by Qing Zhao, Xin Luan, Min Zheng, Xin-Hui Tian, Jing Zhao, Wei-Dong Zhang and Bing-Liang Ma
Pharmaceutics 2020, 12(2), 128; https://doi.org/10.3390/pharmaceutics12020128 - 3 Feb 2020
Cited by 85 | Viewed by 6309
Abstract
The systematic separation strategy has long and widely been applied in the research and development of herbal medicines. However, the pharmacological effects of many bioactive constituents are much weaker than those of the corresponding herbal extracts. Thus, there is a consensus that purer [...] Read more.
The systematic separation strategy has long and widely been applied in the research and development of herbal medicines. However, the pharmacological effects of many bioactive constituents are much weaker than those of the corresponding herbal extracts. Thus, there is a consensus that purer herbal extracts are sometimes less effective. Pharmacological loss of purified constituents is closely associated with their significantly reduced intestinal absorption after oral administration. In this review, pharmacokinetic synergies among constituents in herbal extracts during intestinal absorption were systematically summarized to broaden the general understanding of the pharmaceutical nature of herbal medicines. Briefly, some coexisting constituents including plant-produced primary and secondary metabolites, promote the intestinal absorption of active constituents by improving solubility, inhibiting first-pass elimination mediated by drug-metabolizing enzymes or drug transporters, increasing the membrane permeability of enterocytes, and reversibly opening the paracellular tight junction between enterocytes. Moreover, some coexisting constituents change the forms of bioactive constituents via mechanisms including the formation of natural nanoparticles. This review will focus on explaining this new synergistic mechanism. Thus, herbal extracts can be considered mixtures of bioactive compounds and pharmacokinetic synergists. This review may provide ideas and strategies for further research and development of herbal medicines. Full article
(This article belongs to the Special Issue Intestinal Drug Absorption)
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Other

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8 pages, 979 KiB  
Reply
Reply to “Comment on López-Yerena et al. ‘Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats’ Pharmaceutics 2020, 12, 134”
by Anallely López-Yerena, Anna Vallverdú-Queralt, Raf Mols, Patrick Augustijns, Rosa M. Lamuela-Raventós and Elvira Escribano-Ferrer
Pharmaceutics 2020, 12(12), 1221; https://doi.org/10.3390/pharmaceutics12121221 - 17 Dec 2020
Cited by 2 | Viewed by 1682
Abstract
Recently, in February 2020, we published a study exploring the intestinal absorption and metabolism of oleocanthal (OLC) in rats. A single-pass intestinal perfusion technique (SPIP) was used, involving simultaneous sampling from the luminal perfusate and mesenteric blood. Later, comments on our published paper [...] Read more.
Recently, in February 2020, we published a study exploring the intestinal absorption and metabolism of oleocanthal (OLC) in rats. A single-pass intestinal perfusion technique (SPIP) was used, involving simultaneous sampling from the luminal perfusate and mesenteric blood. Later, comments on our published paper were released, requesting clarification of specific data. In this detailed reply, we hope to have addressed and clarified all the concerns of A. Kaddoumi and K. El Sayed and that the scientific community will benefit from both the study and the comments it has generated. Full article
(This article belongs to the Special Issue Intestinal Drug Absorption)
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2 pages, 197 KiB  
Correction
Correction: López-Yerena, A., et al. “Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats” Pharmaceutics 2020, 12, 134
by Anallely López-Yerena, Anna Vallverdú-Queralt, Raf Mols, Patrick Augustijns, Rosa M. Lamuela-Raventós and Elvira Escribano-Ferrer
Pharmaceutics 2020, 12(12), 1220; https://doi.org/10.3390/pharmaceutics12121220 - 17 Dec 2020
Cited by 2 | Viewed by 1520
Abstract
The authors would like to make the following corrections to this paper [...] Full article
(This article belongs to the Special Issue Intestinal Drug Absorption)
4 pages, 1093 KiB  
Comment
Comment on López-Yerena et al. “Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats” Pharmaceutics 2020, 12, 134
by Amal Kaddoumi and Khalid El Sayed
Pharmaceutics 2020, 12(8), 720; https://doi.org/10.3390/pharmaceutics12080720 - 31 Jul 2020
Cited by 2 | Viewed by 2807
Abstract
This comment is intended to discuss errors observed in the title paper, doi:10.3390/pharmaceutics12020134. When this paper was published, the authors of this commentary were excited to read it. However, the more we read, the more pitfalls were observed, which necessitated a response to [...] Read more.
This comment is intended to discuss errors observed in the title paper, doi:10.3390/pharmaceutics12020134. When this paper was published, the authors of this commentary were excited to read it. However, the more we read, the more pitfalls were observed, which necessitated a response to revise the many errors and misleading information included in this publication. Full article
(This article belongs to the Special Issue Intestinal Drug Absorption)
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