The efflux pump inhibitory properties of (thiolated) polyallylamines

The aim of this study was to investigate efflux pump inhibition by the cationic, non-biodegradable polymer poly(allylamine hydrochloride) and thiolated derivatives, using rhodamine-123 as model substrate. N-acetylcysteine (NAC) was covalently attached to poly(allylamine hydrochloride) (PAH) with a molecular mass of 15 kDa, 70 kDa and to a cross-linked derivative (cPAH). The resulting thiomers were characterized regarding thiol group and disulphide bond content, permeation enhancement across rat intestinal mucosa and safety. Permeation studies showed an up to 1.4-fold improved rhodamine uptake in the presence of 0.5% (m/v) unmodified PAHs. In contrast, an even 1.8-fold improved uptake was achieved in the presence of the corresponding thiomers. Histological observations led to the conclusion that safety of the polymer was not compromised by thiolation. According to these results the thiolated PAH turned out to be a safe tool for oral drug delivery enhancing permeation across the intestinal membrane.