학술논문
An Assessment of the Permeation Enhancer, 1-phenyl-piperazine (PPZ), on Paracellular Flux Across Rat Intestinal Mucosae in Ussing Chambers
Research Paper
Research Paper
Document Type
Academic Journal
Author
Source
Pharmaceutical Research. October 2016, Vol. 33 Issue 10, p2506, 11 p.
Subject
Language
English
ISSN
0724-8741
Abstract
Author(s): V. A. Bzik [sup.1], D. J. Brayden [sup.1] Author Affiliations: (1) grid.7886.1, 0000000107682743, School of Veterinary Medicine and Conway Institute, University College Dublin, , Belfield, Dublin 4, Ireland INTRODUCTION [...]
Purpose 1-phenyl piperazine (PPZ) emerged from a Caco-2 monolayer screen as having high enhancement potential due to a capacity to increase permeation without significant toxicity. Our aim was to further explore the efficacy and toxicity of PPZ in rat ileal and colonic mucosae in order to assess its true translation potential. Methods Intestinal mucosae were mounted in Ussing chambers and apparent permeability coefficient (Papp) values of [.sup.14C]-mannitol and FITC-dextran 4 kDa (FD-4) and transepithelial electrical resistance (TEER) values were obtained following apical addition of PPZ (0.6-60 mM). Exposed issues were assessed for toxicity by histopathology and lactate dehydrogenase (LDH) release. Mucosal recovery after exposure was also assessed using TEER readings. Results PPZ reversibly increased the Papp of both agents across rat ileal and distal colonic mucosae in concentration-dependent fashion, accompanied by TEER reduction, with acceptable levels of tissue damage. The complex mechanism of tight junction opening was part mediated by myosin light chain kinase, stimulation of transepithelial electrogenic chloride secretion, and involved activation of 5-HT.sub.4 receptors. Conclusions PPZ is an efficacious and benign intestinal permeation enhancer in tissue mucosae. However, its active pharmacology suggest that potential for further development in an oral formulation for poorly permeable molecules will be difficult.
Purpose 1-phenyl piperazine (PPZ) emerged from a Caco-2 monolayer screen as having high enhancement potential due to a capacity to increase permeation without significant toxicity. Our aim was to further explore the efficacy and toxicity of PPZ in rat ileal and colonic mucosae in order to assess its true translation potential. Methods Intestinal mucosae were mounted in Ussing chambers and apparent permeability coefficient (Papp) values of [.sup.14C]-mannitol and FITC-dextran 4 kDa (FD-4) and transepithelial electrical resistance (TEER) values were obtained following apical addition of PPZ (0.6-60 mM). Exposed issues were assessed for toxicity by histopathology and lactate dehydrogenase (LDH) release. Mucosal recovery after exposure was also assessed using TEER readings. Results PPZ reversibly increased the Papp of both agents across rat ileal and distal colonic mucosae in concentration-dependent fashion, accompanied by TEER reduction, with acceptable levels of tissue damage. The complex mechanism of tight junction opening was part mediated by myosin light chain kinase, stimulation of transepithelial electrogenic chloride secretion, and involved activation of 5-HT.sub.4 receptors. Conclusions PPZ is an efficacious and benign intestinal permeation enhancer in tissue mucosae. However, its active pharmacology suggest that potential for further development in an oral formulation for poorly permeable molecules will be difficult.