title: In vivo comparison of various polymeric and low molecular mass inhibitors of intestinal P-glycoprotein.
abstract: Several polymers have been reported to modulate drug absorption by inhibition of intestinal P-glycoprotein (P-gp). The aim of the present study was to provide a direct in vivo comparison of delivery systems based on Pluronic P85, Myrj 52 and chitosan-4-thiobutylamidine (Ch-TBA) in vivo in rats, using rhodamine-123 (Rho-123) as representative P-gp substrate. Furthermore, the postulated low molecular mass P-gp inhibitors 6-mercaptopurine and reduced glutathione (GSH) were evaluated in vitro and in vivo. In vitro, the permeation enhancing effect of 6-mercaptopurine, GSH, Pluronic P85, Myrj 52, and the combination of Ch-TBA with GSH was evaluated by using freshly excised rat intestinal mucosa mounted in Ussing-type diffusion chambers. In comparison to buffer only, Rho-123 transport in presence of 100 microm 6-mercaptopurine, 0.5% (w/v) GSH, 0.5% (w/v) Pluronic P85, 0.5% (w/v) Myrj 52 and the combination of 0.5% (w/v) Ch-TBA/ 0.5% (w/v) GSH, was 2.1, 1.6, 1.9, 1.8, 3.0-fold improved, respectively. In vivo in rat, enteric-coated tablets based on Pluronic P85, Myrj 52 or Ch-TBA/GSH increased the area under the plasma concentration time curve (AUC(0-12)) of Rho-123 1.6-fold, 2.4-fold, 4.3-fold, respectively, in comparison to control only. Contrariwise, the low molecular mass excipients 6-mercaptopurine and GSH showed no significant effect in vivo at all. This in vivo study showed that polymeric P-gp inhibitors and especially the delivery system based on thiolated chitosan significantly increased the oral bioavailability of P-gp substrate Rho-123.
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens University Innsbruck, Innrain 52, Josef Möller Haus, A-6020 Innsbruck, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Föger
authors.forename: Herbert
authors.initials: H
authors.lastname: Hoyer
authors.forename: Krum
authors.initials: K
authors.lastname: Kafedjiiski
authors.forename: Michael
authors.initials: M
authors.lastname: Thaurer
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D002686:Chitin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D016503:Drug Delivery Systems; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D010539:Permeability; D011060:Poloxalene / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011108:Polymers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123 / Q000097:blood / Q000378:metabolism; D013608:Tablets, Enteric-Coated / Q000008:administration & dosage
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003692:Delayed-Action Preparations; D011108:Polymers; D013608:Tablets, Enteric-Coated; C493042:chitosan-4-thiobutylamidine; C422648:pluronic block copolymer p85; D002686:Chitin; D020112:Rhodamine 123; D011092:Polyethylene Glycols; D011060:Poloxalene; C009314:polyethylene glycol monostearate