title: Enhanced transport of P-glycoprotein substrate saquinavir in presence of thiolated chitosan.
abstract: It was the aim of this study to investigate the effect of chitosan-4-thiobutylamidine (Ch-TBA) and reduced glutathione (GSH) on the absorption of P-glycoprotein (P-gp) and multidrug resistance protein (MRP) substrate saquinavir in vitro and in vivo. Bidirectional transport studies were performed with Caco-2 cell monolayers and additionally with freshly excised rat small intestinal mucosa mounted in Ussing type chambers. Furthermore, a delivery system based on Ch-TBA and GSH was evaluated in vivo in rats. The functional activity of the efflux pumps in Caco-2 cells and rat intestinal mucosa during the experiment was proven by the efflux ratio of saquinavir, which was 6.4 for Caco-2 cells and 2.1 for rat intestinal mucosa, respectively. Ch-TBA and particularly the combination of Ch-TBA with GSH enhanced apical (AP) absorption and decreased the secretory transport of saquinavir. In presence of 0.5% Ch-TBA and 0.5% GSH, the uptake of saquinavir was 1.6-fold improved in Caco-2 monolayer and 2.1-fold improved in rat intestinal mucosa. In vivo, the area under the plasma concentration time curve (AUC) of saquinavir was 1.4-fold and Cmax 1.6-fold increased, in comparison with control. Results of this study showed that Ch-TBA in combination with GSH can be an interesting tool for increasing the oral bioavailability of actively secreted compounds.
authors: Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens University Innsbruck, Innrain 52, Josef Möller Haus, Innsbruck, A-6020, Austria. florian.foeger@uibk.ac.at
authors: Florian
authors: F
authors: Föger
authors: Krum
authors: K
authors: Kafedjiiski
authors: Herbert
authors: H
authors: Hoyer
authors: Brigitta
authors: B
authors: Loretz
authors: Andreas
authors: A
authors: Bernkop-Schnürch
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D018938:Caco-2 Cells; D048271:Chitosan / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D051381:Rats; D019258:Saquinavir / Q000493:pharmacokinetics*; D013379:Substrate Specificity; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D013438:Sulfhydryl Compounds; D048271:Chitosan; D019258:Saquinavir