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Regional Intestinal Permeability in Rats: A Comparison of Methods
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0002-1525-1430
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0002-5586-2906
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0003-4318-6039
AstraZeneca R&D, Pharmaceut Technol & Dev, S-43183 Gothenburg, Sweden..
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2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4252-4261Article in journal (Refereed) Published
Abstract [en]

Currently, the screening of new drug candidates for intestinal permeation is typically based on in vitro models which give no information regarding regional differences along the gut. When evaluation of intestinal permeability by region is undertaken, two preclinical rat models are commonly used, the Ussing chamber method and single-pass intestinal perfusion (SPIP). To investigate the robustness of in vivo predictions of human intestinal permeability, a set of four model compounds was systematically investigated in both these models, using tissue specimens and segments from the jejunum, ileum, and colon of rats from the same genetic strain. The influence of luminal pH was also determined at two pH levels. Ketoprofen had high and enalaprilat had low effective (P-eff) and apparent (P-app) permeability in all three regions and at both pH levels. Metoprolol had high P-eff in all regions and at both pHs and high P-app at both pHs and in all regions except the jejunum, where P-app was low. Atenolol had low P-eff in all regions and at both pHs, but had high P-app at pH 6.5 and low P-app at pH 7.4. There were good correlations between these rat in situ P-eff (SPIP) and human in vivo P-eff determined previously for the same compounds by both intestinal perfusion of the jejunum and regional intestinal dosing. The results of this study indicate that both investigated models are suitable for determining the regional permeability of the intestine; however, the SPIP model seems to be the more robust and accurate regional permeability model.

Place, publisher, year, edition, pages
2017. Vol. 14, no 12, p. 4252-4261
Keywords [en]
intestinal permeability, Ussing chamber method, single-pass intestinal perfusion, jejunum, ileum, colon, rat
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-345176DOI: 10.1021/acs.molpharmaceut.7b00279ISI: 000417342400014PubMedID: 28920690OAI: oai:DiVA.org:uu-345176DiVA, id: diva2:1188757
Funder
EU, FP7, Seventh Framework Programme, FP7/2007-013Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-10-20Bibliographically approved
In thesis
1. Intestinal absorption of drugs: The impact of regional permeability, nanoparticles, and absorption-modifying excipients
Open this publication in new window or tab >>Intestinal absorption of drugs: The impact of regional permeability, nanoparticles, and absorption-modifying excipients
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

For successful delivery of orally given drug products, the drug compounds must have adequate solubility and permeability in the human gastrointestinal tract. The permeability of a compound is determined by its size and lipophilicity, and is usually evaluated in various pre-clinical models, including rat models.

This thesis had three major aims: 1) investigate regional permeability in human and rat intestines and evaluate two different rat models, 2) investigate the mechanisms behind absorption in nanosuspensions, and 3) investigate the effect of food on the absorption of drug molecules in solutions and suspensions, and also food’s effect on absorption modifying excipients (AMEs).

Effective human permeability values obtained using regional intra-intestinal dosing and a deconvolution method agreed with values established by perfusion from the jejunum, demonstrating the accuracy and validity of the intra-intestinal bolus-dosing approach. Single-pass intestinal perfusion (SPIP) in rats showed better correlation with human effective permeability than the Ussing chamber, and was therefore deemed the better model for predicting drug permeability in humans.

Absorption of microsuspensions and nanosuspension was investigated using rat SPIP, which showed that microsuspensions are subject to pronounced food effects, probably by partitioning of drug into the colloidal structures formed by bile acids, lecithin, and fatty acids. Nanosuspensions were less affected by food, which was attributed to fewer available nanoparticles in the fed state due to partitioning into colloidal structures, and because nanoparticles are able to cross the aqueous boundary layer on their own, increasing the concentration of drug adjacent to the epithelial membrane.

AMEs had less effect in the fed state than the fasted state when investigated using SPIP. This difference may be caused by AMEs partitioning into luminal colloidal structures, decreasing the AMEs’ effects on the intestinal membrane. It thus seems that AMEs as well as drug compounds are subject to food-drug interactions, which may either increase or decrease the effect or absorption, something that needs to be considered during development of new drug products. 

In summary, this thesis has improved the knowledge of pre-clinical absorption models and the understanding of several biopharmaceutical mechanisms important for drug absorption.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 73
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 260
Keywords
Permeability, intestinal absorption, regional permeability, nanoparticles, nanosuspensions, absorption-modifying excipients, AMEs
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-363908 (URN)978-91-513-0484-7 (ISBN)
Public defence
2018-12-07, A1:107A, Uppsala Biomedical Centre, Husargatan 3, Uppsala, 09:15 (English)
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Available from: 2018-11-14 Created: 2018-10-20 Last updated: 2018-11-30

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Roos, CarlDahlgren, DavidSjögren, ErikLennernäs, Hans

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