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Regional Intestinal Permeability in Dogs: Biopharmaceutical Aspects for Development of Oral Modified-Release Dosage Forms
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
AstraZeneca R&D, SE-43150 Gothenburg, Sweden..
AstraZeneca R&D, SE-43150 Gothenburg, Sweden..
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2016 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 9, 3022-3033 p.Article in journal (Refereed) Published
Abstract [en]

The development of oral modified-release (MR) dosage forms requires an active pharmaceutical ingredient (API) with a sufficiently high absorption rate in both the small and large intestine. Dogs are commonly used in preclinical evaluation of regional intestinal absorption and in the development of novel MR dosage forms. This study determined regional intestinal effective permeability (P-eff) in dogs with the aim to improve regional Peff prediction in humans. Four model drugs, atenolol, enalaprilat, metoprolol, and ketoprofen, were intravenously and regionally dosed twice as a solution into the proximal small intestine (P-SI) and large intestine (LI) of three dogs with intestinal stomas. Based on plasma data from two separate study occasions for each dog, regional Peff values were calculated using a validated intestinal deconvolution method. The determined mean P-eff values were 0.62, 0.14, 1.06, and 3.66 X 10(-4) cm/s in the P-SI, and 0.13, 0.02, 1.03, and 2.20 X 10(-4) cm/s in the LI, for atenolol, enalaprilat, metoprolol, and ketoprofen, respectively. The determined P-SI Peff values in dog were highly correlated (R-2 = 0.98) to the historically directly determined human jejunal P-eff after a single-pass perfusion. The determined dog P-SI P-eff values were also successfully implemented in GI-Sim to predict the risk for overestimation of LI absorption of low permeability drugs. We conclude that the dog intestinal stoma model is a useful preclinical tool for determination of regional intestinal permeability. Still, further studies are recommended to evaluate additional APIs, sources of variability, and formulation types, for more accurate determination of the dog model in the drug development process.

Place, publisher, year, edition, pages
2016. Vol. 13, no 9, 3022-3033 p.
Keyword [en]
dog intestinal permeability, regional intestinal drug absorption, bioavailability, effective permeability, pharmacokinetics, intestinal perfusion, pharmaceutical development
National Category
Veterinary Science Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-307865DOI: 10.1021/acs.molpharmaceut.6b00515ISI: 000382713700017PubMedID: 27500599OAI: oai:DiVA.org:uu-307865DiVA: diva2:1048905
Funder
EU, European Research Council, FP7/2007-013
Available from: 2016-11-22 Created: 2016-11-22 Last updated: 2016-11-22Bibliographically approved

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Dahlgren, DavidRoos, CarlSjögren, ErikLennernäs, Hans
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