title: Glutathione and thiolated chitosan inhibit multidrug resistance P-glycoprotein activity in excised small intestine.
abstract: The aim of the present study was to evaluate the influence of glutathione (GSH), the thiomer chitosan-4-thiobutylamidine (chitosan-TBA) and a combination of both compounds on P-glycoprotein (P-gp) activity. Permeation studies were performed with freshly excised guinea pig ileum mounted in Ussing chambers using the fluorescent dye rhodamine-123 (Rho-123) as P-gp substrate. Apparent permeability coefficients (Papp) as well as efflux ratios (secretory Papp/absorptive Papp) were calculated and compared with values gained from experiments with the well-established P-gp inhibitors terfenadine and verapamil. In the presence of terfenadine, verapamil as well as GSH, the absorptive transport of Rho-123 across intestinal tissue increased, while the secretory decreased with efflux ratios around 1.0. Chitosan-TBA and especially chitosan-TBA/GSH not only enhanced absorption of Rho-123, but also reduced the basolateral to apical secretion of Rho-123 resulting in efflux ratios of 1.1, 0.8 and 0.5. The study indicates that chitosan-TBA/GSH is a potentially valuable tool for inhibiting the ATPase activity of P-gp in the intestine.
authors.affiliation: ThioMatrix Forschung- und Beratungs-GmbH, Mitterweg 24, 6020 Innsbruck, Austria. m.werle@thiomatrix.com
authors.forename: Martin
authors.initials: M
authors.lastname: Werle
authors.forename: Martin
authors.initials: M
authors.lastname: Hoffer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D048271:Chitosan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D005978:Glutathione / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D015203:Reproducibility of Results; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D016593:Terfenadine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D013438:Sulfhydryl Compounds; C510275:chitosan 2-iminothiolane; D020112:Rhodamine 123; D016593:Terfenadine; D048271:Chitosan; D014700:Verapamil; D005978:Glutathione