Thiolated chitosans: influence of various sulfhydryl ligands on permeation-enhancing and P-gp inhibitory properties

Abstract

Purpose: The influence of various sulfhydryl ligands on permeation-enhancing and P-glycoprotein (P-gp) inhibitory properties of the six established thiolated chitosan conjugates was investigated using Rhodamine-123 (Rho-123) and fluorescein isothiocyanate-dextran 4 (FD4) as model compounds. Methods: Permeation of these compounds was tested on freshly excised rat intestine in Ussing-type chambers. Apparent permeability coefficients (Papp) were calculated and compared to values obtained from the buffer only control. Results: The lyophilized polymers had a thiol group content in the range of 230–520 μmol/g. Results of this study led to the following rank order in permeation enhancement: chitosan-6-mercaptonicotinic acid (chitosan-6MNA) > chitosan-cysteine (chitosan-Cys) > chitosan-glutathione (chitosan-GSH) > chitosan-4-thiobutylamidine (chitosan-TBA) > chitosan-thioglycolic acid (chitosan-TGA) > chitosan-N-acetyl cysteine (chitosan-NAC). In P-gp inhibition studies, 0.5% (m/v) chitosan-NAC showed the highest inhibitory effect on P-gp, where the Papp was determined to be 3.78-fold increased compared with the buffer control. Among these thiolated chitosans, chitosan-NAC and chitosan-6MNA are the most effective polymers being responsible for P-gp inhibition and permeation enhancement, respectively. Conclusion: These thiolated chitosans would therefore be advantageous tools for enhancing the noninvasive bioavailability of active pharmaceutical ingredients.

Keywords::

• Drug absorption
• efflux pump inhibition
• permeation enhancing effect
• thiolated chitosans
• thiomers

Acknowledgments

The Nano-Health project (No. 0200) as part of the Austrian Nano-Initiative was financed by the Austrian FFG (Forschungsförderungsgesellschaft mbH) (Project No. 819721).

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.