title: Thiomers: Influence of molecular mass and thiol group content of poly(acrylic acid) on efflux pump inhibition.
abstract: The aim of the present study was to investigate the influence of molecular mass and thiol group content of poly(acrylic acid)-cysteine conjugates on the permeation of sulforhodamine 101 and penicillin G. acting as substrates for multidrug resistance-associated protein 2 efflux pump. Poly(acrylic acids) of 2 kDa, 100 kDa, 250 kDa, 450 kDa and 3000 kDa were conjugated with cysteine. The thiol group content of all these polymers was in the range from 343.3 ± 48.4 μmol/g to 450.3 ± 76.1 μmol/g. Transport studies were performed on rat small intestine mounted in Ussing-type chambers. Since 250 kDa poly(acrylic acid) showed the highest permeation enhancing effect, additionally thiolated 250 kDa polyacrylates displaying 157.2 μmol/g, 223.0 ± 18.1 and 355.9 μmol/g thiol groups were synthesized in order to investigate the influence of thiol group content on the permeation enhancement. The permeation of sulforhodamine was 3.93- and 3.85-fold improved using 250 kDa poly(acrylic acid)-cysteine conjugate exhibiting 355.9 ± 39.5 μmol/g and 223.0 ± 18.1 μmol/g thiol groups. Using the same conjugates the permeation of penicillin G was 1.70- and 1.59-fold improved, respectively. The study demonstrates that thiolated poly(acrylic acid) inhibits Mrp2 mediated transport and that the extent of inhibition depends on the molecular mass and degree of thiolation of the polymer.
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Austria.
authors.forename: Vjera
authors.initials: V
authors.lastname: Grabovac
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Austria.
authors.forename: Flavia
authors.initials: F
authors.lastname: Laffleur
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Austria. Electronic address: Andreas.Bernkop@uibk.ac.at.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D066298:In Vitro Techniques; D007583:Jejunum / Q000378:metabolism; D008297:Male; D008970:Molecular Weight; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010400:Penicillin G / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability; D017207:Rats, Sprague-Dawley; D012235:Rhodamines / Q000737:chemistry / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000180:Acrylic Resins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010400:Penicillin G; D012235:Rhodamines; D013438:Sulfhydryl Compounds; C006903:carbopol 940; C050829:sulforhodamine 101
keywords: Inhibition; Molecular mass; Mrp2; Permeation; Poly(acrylic acid)