title: Development of an ion-pair to improve the colon permeability of a low permeability drug: Atenolol.
abstract: To ensure the optimal performance of oral controlled release formulations, drug colon permeability is one of the critical parameters. Consequently developing this kind of formulations for low permeability molecules requires strategies to increase their ability to cross the colonic membrane. The objective of this work is to show if an ion-pair formation can improve the colon permeability of atenolol as a low permeability drug model. Two counter ions have been tested: brilliant blue and bromophenol blue. The Distribution coefficients at pH7.00 (DpH7) of atenolol, atenolol + brilliant blue and atenolol + bromophenol blue were experimentally determined in n-octanol. Moreover, the colonic permeability was determined in rat colon using in situ closed loop perfusion method based in Doluisio's Technique. To check the potential effects of the counter ions on the membrane integrity, a histological assessment of colonic tissue was done. The results of the partitioning studies were inconclusive about ion-pair formation; nevertheless colon permeability was significantly increased by both counter ions (from 0.232±0.021cm/s to 0.508±0.038cm/s in the presence of brilliant blue and to 0.405±0.044cm/s in the presence of bromophenol blue). Neither damage on the membrane was observed on the histological studies, nor any change on paracellular permeability suggesting that the permeability enhancement could be attributed to the ion-pair formation.
authors.affiliation: Pharmacokinetics and Pharmaceutical Technology, Miguel Hernandez University, Spain; Pharmacokinetics and Pharmaceutical Technology, University of Valencia, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Lozoya-Agullo
authors.affiliation: Pharmacokinetics and Pharmaceutical Technology, Miguel Hernandez University, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: González-Álvarez
authors.affiliation: Pharmacokinetics and Pharmaceutical Technology, Miguel Hernandez University, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: González-Álvarez
authors.affiliation: Pharmacokinetics and Pharmaceutical Technology, University of Valencia, Spain; Molecular Recognition and Technological Development, Polytechnic University-University of Valencia, Valencia, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Merino-Sanjuán
authors.affiliation: Pharmacokinetics and Pharmaceutical Technology, Miguel Hernandez University, Spain. Electronic address: mbermejo@umh.es.
authors.forename: Marival
authors.initials: M
authors.lastname: Bermejo
mesh_terms: D000818:Animals; D001262:Atenolol / Q000378:metabolism*; D001557:Benzenesulfonates / Q000378:metabolism; D001978:Bromphenol Blue / Q000378:metabolism; D003106:Colon / Q000378:metabolism*; D004396:Coloring Agents / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000378:metabolism; D008297:Male; D010539:Permeability; D017208:Rats, Wistar
chemical_list: D001557:Benzenesulfonates; D004396:Coloring Agents; D003692:Delayed-Action Preparations; D001978:Bromphenol Blue; D001262:Atenolol; C006796:brilliant blue
keywords: Atenolol; Colonic permeability; Counter ion; Ion-pair; Low permeability drugs