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Effect of absorption-modifying excipients, hypotonicity, and enteric neural activity in an in vivo model for small intestinal transport.
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: 0000-0002-1525-1430
AstraZeneca R&D, Gothenburg, Sweden.
AstraZeneca R&D, Gothenburg, Sweden.
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2018 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 549, no 1-2, p. 239-248, article id S0378-5173(18)30532-5Article in journal (Refereed) Published
Abstract [en]

The small intestine mucosal barrier is physiologically regulated by the luminal conditions, where intestinal factors, such as diet and luminal tonicity, can affect mucosal permeability. The intestinal barrier may also be affected by absorption-modifying excipients (AME) in oral drug delivery systems. Currently, there is a gap in the understanding of how AMEs interact with the physiological regulation of intestinal electrolyte transport and fluid flux, and epithelial permeability. Therefore, the objective of this single-pass perfusion study in rat was to investigate the effect of three AMEs on the intestinal mucosal permeability at different luminal tonicities (100, 170, and 290 mOsm). The effect was also evaluated following luminal administration of a nicotinic receptor antagonist, mecamylamine, and after intravenous administration of a COX-2 inhibitor, parecoxib, both of which affect the enteric neural activity involved in physiological regulation of intestinal functions. The effect was evaluated by changes in intestinal lumen-to-blood transport of six model compounds, and blood-to-lumen clearance of 51Cr-EDTA (a mucosal barrier marker). Luminal hypotonicity alone increased the intestinal epithelial transport of 51Cr-EDTA. This effect was potentiated by two AMEs (SDS and caprate) and by parecoxib, while it was reduced by mecamylamine. Consequently, the impact of enteric neural activity and luminal conditions may affect nonclinical determinations of intestinal permeability. In vivo predictions based on animal intestinal perfusion models can be improved by considering these effects. The in vivo relevance can be increased by treating rats with a COX-2 inhibitor prior to surgery. This decreases the risk of surgery-induced ileus, which may affect the physiological regulation of mucosal permeability.

Place, publisher, year, edition, pages
2018. Vol. 549, no 1-2, p. 239-248, article id S0378-5173(18)30532-5
Keywords [en]
Absorption-modifying excipients, Biopharmaceutical classification system, In vivo predictions, Intestinal perfusion, Intestinal permeability, Intestinal physiology, Permeation enhancers
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
URN: urn:nbn:se:uu:diva-358464DOI: 10.1016/j.ijpharm.2018.07.057ISI: 000443255300022PubMedID: 30055302OAI: oai:DiVA.org:uu-358464DiVA, id: diva2:1242811
Available from: 2018-08-29 Created: 2018-08-29 Last updated: 2018-11-19Bibliographically approved
In thesis
1. Biopharmaceutical aspects of intestinal drug absorption: Regional permeability and absorption-modifying excipients
Open this publication in new window or tab >>Biopharmaceutical aspects of intestinal drug absorption: Regional permeability and absorption-modifying excipients
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Before an orally administered drug reaches the systemic circulation, it has to dissolve in the intestinal fluids, permeate across the intestinal epithelial cell barrier, and pass through the liver. The permeation rate of drug compounds can be low and show regional differences.

The thesis had two general aims. The first of these was, to determine and compare regional intestinal permeability values of model compounds in human and dog. The second was to understand the possible effects of absorption-modifying pharmaceutical excipients (AMEs) on the intestinal permeability of the model compounds. The usefulness of several preclinical animal models for predicting the impact of regional intestinal permeability and AMEs in human was also investigated.

There was a good correlation between human and dog permeability values in the small intestines for the model compounds. The colon in dog was substantially more permeable than the human colon to the low permeability drug, atenolol. This difference in colonic permeability may have implications for the use of dog as a model species for prediction of human intestinal drug absorption.

There were no effects of AMEs on the intestinal permeability of any of the high permeability compounds, in any animal model. In the rat single-pass intestinal perfusion model, there was a substantial increase in permeability of all low permeability drugs, induced by two AMEs, chitosan and SDS. This AME-induced increase was substantially lower in the more in vivo relevant rat and dog intraintestinal bolus models. A shorter AME exposure-time in the rat single-pass intestinal perfusion model (15 vs. 75 min) could, however, predict the result from the bolus studies in rat and dog. This illustrates the impact of intestinal transit and mucosal exposure time on AME effects in vivo. The intestinal luminal conditions and enteric neural activity also had an impact on determinations of drug permeability in the rat single-pass intestinal perfusion model, which can have implications for its in vivo relevance.

In summary, this thesis used multiple in vivo models to evaluate the impact of several biopharmaceutical processes on intestinal drug absorption. This has led to an increased understanding of these absorption mechanisms.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 68
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 257
Keywords
intestinal permeability, absorption-modifying excipients
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-358467 (URN)978-91-513-0442-7 (ISBN)
Public defence
2018-11-02, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-10-10 Created: 2018-09-12 Last updated: 2018-10-16

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Dahlgren, DavidRoos, CarlSjöblom, MarkusSjögren, ErikLennernäs, Hans

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