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The effects of three absorption-modifying critical excipients on the in vivo intestinal absorption of six model compounds in rats and dogs.
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
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2018 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 547, no 1-2, p. 158-168Article in journal (Refereed) Published
Abstract [en]

Pharmaceutical excipients that may affect gastrointestinal (GI) drug absorption are called critical pharmaceutical excipients, or absorption-modifying excipients (AMEs) if they act by altering the integrity of the intestinal epithelial cell membrane. Some of these excipients increase intestinal permeability, and subsequently the absorption and bioavailability of the drug. This could have implications for both the assessment of bioequivalence and the efficacy of the absorption-enhancing drug delivery system. The absorption-enhancing effects of AMEs with different mechanisms (chitosan, sodium caprate, sodium dodecyl sulfate (SDS)) have previously been evaluated in the rat single-pass intestinal perfusion (SPIP) model. However, it remains unclear whether these SPIP data are predictive in a more in vivo like model. The same excipients were in this study evaluated in rat and dog intraintestinal bolus models. SDS and chitosan did exert an absorption-enhancing effect in both bolus models, but the effect was substantially lower than those observed in the rat SPIP model. This illustrates the complexity of the AME effects, and indicates that additional GI physiological factors need to be considered in their evaluation. We therefore recommend that AME evaluations obtained in transit-independent, preclinical permeability models (e.g. Ussing, SPIP) should be verified in animal models better able to predict in vivo relevant GI effects, at multiple excipient concentrations.

Place, publisher, year, edition, pages
2018. Vol. 547, no 1-2, p. 158-168
Keywords [en]
Absorption modifiers, Bioequivalence, Intraintestinal administration, Permeation enhancers, Pharmaceutical development
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
URN: urn:nbn:se:uu:diva-358463DOI: 10.1016/j.ijpharm.2018.05.029ISI: 000439096500016PubMedID: 29758344OAI: oai:DiVA.org:uu-358463DiVA, id: diva2:1242813
Available from: 2018-08-29 Created: 2018-08-29 Last updated: 2018-09-28Bibliographically 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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