title: Thiolated chitosans: influence of various sulfhydryl ligands on permeation-enhancing and P-gp inhibitory properties.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  These thiolated chitosans would therefore be advantageous tools for enhancing the noninvasive bioavailability of active pharmaceutical ingredients.
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria.
authors.forename: Duangkamon
authors.initials: D
authors.lastname: Sakloetsakun
authors.forename: Javed
authors.initials: J
authors.lastname: Iqbal
authors.forename: Gioconda
authors.initials: G
authors.lastname: Millotti
authors.forename: Anja
authors.initials: A
authors.lastname: Vetter
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; D048271:Chitosan / Q000737:chemistry* / Q000494:pharmacology; D003911:Dextrans / Q000008:administration & dosage / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry* / Q000494:pharmacology; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000493:pharmacokinetics; D005612:Freeze Drying; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000008:administration & dosage / Q000493:pharmacokinetics; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003911:Dextrans; D004337:Drug Carriers; D005456:Fluorescent Dyes; D013438:Sulfhydryl Compounds; C015219:fluorescein isothiocyanate dextran; D020112:Rhodamine 123; D048271:Chitosan; D016650:Fluorescein-5-isothiocyanate