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Preclinical Effect of Absorption Modifying Excipients on Rat Intestinal Transport of Model Compounds and the Mucosal Barrier Marker 51Cr-EDTA
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.ORCID-id: 0000-0002-5586-2906
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.ORCID-id: 0000-0002-1525-1430
AstraZeneca R&D.
AstraZeneca R&D.
Vise andre og tillknytning
2017 (engelsk)Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, nr 12, s. 4243-4251Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

There is a renewed interest from the pharmaceutical field to develop oral formulations of compounds, such as peptides, oligonucleotides, and polar drugs. However, these often suffer from insufficient absorption across the intestinal mucosal barrier. One approach to circumvent this problem is the use of absorption modifying excipient(s) (AME). This study determined the absorption enhancing effect of four AMEs (sodium dodecyl sulfate, caprate, chitosan, N-acetylcysteine) on five model compounds in a rat jejunal perfusion model. The aim was to correlate the model compound absorption to the blood-to-lumen clearance of the mucosal marker for barrier integrity, 51Cr-EDTA. Sodium dodecyl sulfate and chitosan increased the absorption of the low permeation compounds but had no effect on the high permeation compound, ketoprofen. Caprate and N-acetylcysteine did not affect the absorption of any of the model compounds. The increase in absorption of the model compounds was highly correlated to an increased blood-to-lumen clearance of 51Cr-EDTA, independent of the AME. Thus, 51Cr-EDTA could be used as a general, sensitive, and validated marker molecule for absorption enhancement when developing novel formulations.

sted, utgiver, år, opplag, sider
2017. Vol. 14, nr 12, s. 4243-4251
Emneord [en]
absorption modifiers, bioequivalence, intestinal perfusion, permeation enhancers, pharmaceutical development
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-343167DOI: 10.1021/acs.molpharmaceut.7b00353ISI: 000417342400013PubMedID: 28737406OAI: oai:DiVA.org:uu-343167DiVA, id: diva2:1185605
Forskningsfinansiär
EU, FP7, Seventh Framework Programme, FP7/2007-013Tilgjengelig fra: 2018-02-26 Laget: 2018-02-26 Sist oppdatert: 2018-09-12bibliografisk kontrollert
Inngår i avhandling
1. Biopharmaceutical aspects of intestinal drug absorption: Regional permeability and absorption-modifying excipients
Åpne denne publikasjonen i ny fane eller vindu >>Biopharmaceutical aspects of intestinal drug absorption: Regional permeability and absorption-modifying excipients
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 68
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 257
Emneord
intestinal permeability, absorption-modifying excipients
HSV kategori
Forskningsprogram
Biofarmaci
Identifikatorer
urn:nbn:se:uu:diva-358467 (URN)978-91-513-0442-7 (ISBN)
Disputas
2018-11-02, B41, BMC, Husargatan 3, Uppsala, 09:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-10-10 Laget: 2018-09-12 Sist oppdatert: 2018-10-16

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