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Open AccessArticle

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

1
Department of Pharmacy, Division of Biopharmaceutics, Uppsala University, 752 36 Uppsala, Sweden
2
Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46010 València, Spain
3
Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry, Uppsala University, 752 36 Uppsala, Sweden
4
Department of Chemistry, Environment and Feed Hygiene, National Veterinary Institute (SVA), 751 89 Uppsala, Sweden
5
Department of Neuroscience, Division of Physiology, Uppsala University, 752 36 Uppsala, Sweden
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(3), 242; https://doi.org/10.3390/pharmaceutics12030242
Received: 23 January 2020 / Revised: 26 February 2020 / Accepted: 3 March 2020 / Published: 8 March 2020
(This article belongs to the Special Issue Regional Intestinal Drug: Biopharmaceutics and Drug Formulation)
Sufficient colonic absorption is necessary for all systemically acting drugs in dosage forms that release the drug in the large intestine. Preclinically, colonic absorption is often investigated using the rat single-pass intestinal perfusion model. This model can determine intestinal permeability based on luminal drug disappearance, as well as the effect of permeation enhancers on drug permeability. However, it is uncertain how accurate the rat single-pass intestinal perfusion model predicts regional intestinal permeability and absorption in human. There is also a shortage of systematic in vivo investigations of the direct effect of permeation enhancers in the small and large intestine. In this rat single-pass intestinal perfusion study, the jejunal and colonic permeability of two low permeability drugs (atenolol and enalaprilat) and two high-permeability ones (ketoprofen and metoprolol) was determined based on plasma appearance. These values were compared to already available corresponding human data from a study conducted in our lab. The colonic effect of four permeation enhancers—sodium dodecyl sulfate, chitosan, ethylenediaminetetraacetic acid (EDTA), and caprate—on drug permeability and transport of chromium EDTA (an established clinical marker for intestinal barrier integrity) was determined. There was no difference in jejunal and colonic permeability determined from plasma appearance data of any of the four model drugs. This questions the validity of the rat single-pass intestinal perfusion model for predicting human regional intestinal permeability. It was also shown that the effect of permeation enhancers on drug permeability in the colon was similar to previously reported data from the rat jejunum, whereas the transport of chromium EDTA was significantly higher (p < 0.05) in the colon than in jejunum. Therefore, the use of permeation enhancers for increasing colonic drug permeability has greater risks than potential medical rewards, as indicated by the higher permeation of chromium EDTA compared to the drugs. View Full-Text
Keywords: regional intestinal permeability; permeation enhancers; absorption-modifying excipients; oral peptide delivery; intestinal perfusion; pharmaceutical development regional intestinal permeability; permeation enhancers; absorption-modifying excipients; oral peptide delivery; intestinal perfusion; pharmaceutical development
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Dahlgren, D.; Cano-Cebrián, M.-J.; Olander, T.; Hedeland, M.; Sjöblom, M.; Lennernäs, H. Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat. Pharmaceutics 2020, 12, 242.

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