Intestinal permeability and its relevance for absorption and elimination
Abstract
Human jejunal permeability (P(eff)) is determined in the intestinal region with the highest expression of carrier proteins and largest surface area. Intestinal P(eff) are often based on multiple parallel transport processes. Site-specific jejunal P(eff) cannot reflect the permeability along the intestinal tract, but they are useful for approximating the fraction oral dose absorbed. It seems like drugs with a jejunal P(eff) > 1.5 x 10(-4) cm s(-1) will be completely absorbed no matter which transport mechanism(s) are utilized. Many drugs that are significantly effluxed in vitro have a rapid and complete intestinal absorption (i.e. >85%) mediated by passive transcellular diffusion. The determined jejunal P(eff) for drugs transported mainly by absorptive carriers (such as peptide and amino acid transporters) will accurately predict the fraction of the dose absorbed as a consequence of the regional expression. The data also show that: (1) the human intestinal epithelium has a large resistance towards large and hydrophilic compounds; and (2) the paracellular route has a low contribution for compounds larger than approximately molecular weight 200. There is a need for more exploratory in vivo studies to clarify drug absorption and first-pass extraction along the intestine. One is encouraged to develop in vivo perfusion techniques for more distal parts of the gastrointestinal tract in humans. This would stimulate the development of more relevant and complex in vitro absorption models and form the basis for an accurate physiologically based pharmacokinetic modelling of oral drug absorption.
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The paracellular route may contribute to LT4 absorption.
“In addition, the paracellular route may contribute to LT4 absorption (28).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [28]
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Improving outcomes in patients with adrenal insufficiency: a review of current and future treatments
Johannsson, G., Skrtic, S., Lennernäs, H., Quinkler, M., & Stewart, P. M. (2014) · Current Medical Research and Opinion · doi:10.1185/03007995.2014.925865 · Cited by 21 · see citing works
Self-citationHeikkinen, A. T., Fowler, S., Gray, L., Li, J., Peng, Y., Yadava, P., Railkar, A., & Parrott, N. (2013) · Molecular Pharmaceutics · doi:10.1021/mp300692k · Cited by 20 · see citing works
Early ADME/T Predictions: Toy or Tool?
Tetko, I. V., & Oprea, T. I. (2008) · Chemoinformatics Approaches to Virtual Screening · doi:10.1039/9781847558879-00240 · Cited by 5 · see citing works
- Authors
- Lennernäs, H.
- Affiliations
- Uppsala University (SE)
- Corresponding author
- Lennernäs, H.
- ORCID
- Lennernäs, H.
- Venue
- Xenobiotica
- Publisher
- Informa UK Limited
- Published
- 2007-11
- Volume
- 37
- Issue
- 10-11
- Pages
- 1015-1051
- ISSN
- 0049-8254 (ISSN-L)
- 1366-5928
- OpenAlex
- W2007052092
- Cited by
- 304
- References
- 199
- Citations by year
- 2026: 14 · 2025: 21 · 2024: 15 · 2023: 16 · 2022: 16 · 2021: 20 · 2020: 15 · 2019: 16 · 2018: 19 · 2017: 8 · 2016: 13 · 2015: 13 · 2014: 20 · 2013: 16 · 2012: 24
- FWCI
- 11.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Xenobiotica (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- intestinal permeability, oral drug absorption, paracellular transport, efflux pumps, first-pass extraction, in vivo perfusion, physiologically based pharmacokinetic modelling, in vitro absorption model, human intestinal epithelium
- MeSH terms
- Biological Transport, Active, Carrier Proteins, Humans, Intestinal Absorption, Jejunum, Models, Biological, Permeability, Xenobiotics
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