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Mol Pharm. 2017 Dec 4;14(12):4243-4251. doi: 10.1021/acs.molpharmaceut.7b00353. Epub 2017 Aug 8.

Preclinical Effect of Absorption Modifying Excipients on Rat Intestinal Transport of Model Compounds and the Mucosal Barrier Marker 51Cr-EDTA.

Author information

1
Department of Pharmacy, Uppsala University , 751 24 Uppsala, Sweden.
2
AstraZeneca R&D , 431 50 Mölndal, Sweden.
3
School of Pharmacy, Johannes Gutenberg-University , 55122 Mainz, Germany.
4
Department of Neuroscience, Division of Physiology, Uppsala University , 752 36 Uppsala, Sweden.

Abstract

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.

KEYWORDS:

absorption modifiers; bioequivalence; intestinal perfusion; permeation enhancers; pharmaceutical development

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