MilliporeSigma
  • Home
  • Search Results
  • In vivo evaluation of anionic thiolated polymers as oral delivery systems for efflux pump inhibition.

In vivo evaluation of anionic thiolated polymers as oral delivery systems for efflux pump inhibition.

International journal of pharmaceutics (2015-06-23)
Thomas F Palmberger, Flavia Laffleur, Melanie Greindl, Andreas Bernkop-Schnürch
ABSTRACT

Recently, the cationic polymer thiolated chitosan has been reported to modulate drug absorption by inhibition of intestinal efflux pumps. The objective of this study was to evaluate in vitro and in vivo whether thiolated anionic biopolymers also show an efflux pump inhibitory effect in order to improve intestinal transcellular drug uptake. Therefore, three thiomers have been synthesized due covalent attachment of cysteine to various polymer backbones: pectin-cysteine (pect-cys), carboxymethylcellulose-cysteine (CMC-cys) and alginate-cysteine (alg-cys). In vitro, the permeation enhancing properties of these thiomers and their corresponding unmodified polymers have been evaluated on rat small intestine in Ussing-type chambers, using sulforhodamine 101 (SR-101) as MRP2 model substrate. In comparison to buffer only, SR-101 transport in presence of pect-cys, CMC-cys and alg-cys was improved 1.5-fold, 1.8-fold and 3.0-fold, respectively. Due to the comparatively best in vitro performance of thiolated alginate, it has been chosen for in vivo studies: a SR-101 solution containing 4% (w/v) alg-cys led to an AUC0 ≥ 12 of SR-101 of 109 ng ml(-1)h in rats representing a 3.8-fold improvement in comparison to a SR-101 buffer solution. Unmodified alginate improved the AUC0 ≥ 12 of SR-101 by a factor of 1.9. These findings suggest thiolated alginate as promising auxiliary agent for drugs being anionic efflux pump substrates, since the oral bioavailability of a MRP2 substrate could be significantly improved.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sulforhodamine 101
Sigma-Aldrich
Picrylsulfonic acid solution, 5 % (w/v) in H2O, BioReagent, suitable for determination of primary amines
Sigma-Aldrich
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, commercial grade, powder
Sigma-Aldrich
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, crystalline
Sigma-Aldrich
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, BioXtra
Sigma-Aldrich
L-Glutathione reduced, BioXtra, ≥98.0%
Sigma-Aldrich
L-Cysteine, from non-animal source, BioReagent, suitable for cell culture, ≥98%
Sigma-Aldrich
L-Glutathione reduced, suitable for cell culture, BioReagent, ≥98.0%, powder
Sigma-Aldrich
L-Glutathione reduced, ≥98.0%
SAFC
L-Cysteine
Sigma-Aldrich
L-Cysteine, BioUltra, ≥98.5% (RT)
Sigma-Aldrich
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, ≥99.0% (AT)
Sigma-Aldrich
Ethanesulfonic acid solution, 70 wt. % in H2O
Sigma-Aldrich
L-Cysteine, 97%
Sigma-Aldrich
Ethanesulfonic acid, 95%
Sigma-Aldrich
L-Cysteine, ≥97%, FG
Sigma-Aldrich
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide, ≥97.0% (T)
Sigma-Aldrich
L-Cysteine, produced by Wacker Chemie AG, Burghausen, Germany, ≥98.0%
Sigma-Aldrich
5,5′-Dithiobis(2-nitrobenzoic acid), ReagentPlus®, 99%
Sigma-Aldrich
HEPES buffer solution, 1 M in H2O
Sigma-Aldrich
HEPES, BioUltra, for molecular biology, ≥99.5% (T)
Sigma-Aldrich
HEPES, BioXtra, pH 5.0-6.5 (1 M in H2O), ≥99.5% (titration)
Sigma-Aldrich
HEPES, BioPerformance Certified, ≥99.5% (titration), suitable for cell culture
Sigma-Aldrich
5,5′-Dithiobis(2-nitrobenzoic acid), ≥98%, BioReagent, suitable for determination of sulfhydryl groups
Sigma-Aldrich
HEPES, BioXtra, suitable for mouse embryo cell culture, ≥99.5% (titration)
Sigma-Aldrich
HEPES, ≥99.5% (titration)
Sigma-Aldrich
HEPES, anhydrous, free-flowing, Redi-Dri, ≥99.5%
SAFC
HEPES
SAFC
HEPES