Investigations of Piperazine Derivatives as Intestinal Permeation Enhancers in Isolated Rat Intestinal Tissue Mucosae

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Title: Investigations of Piperazine Derivatives as Intestinal Permeation Enhancers in Isolated Rat Intestinal Tissue Mucosae
Authors: Stuettgen, VivienBrayden, David James
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Date: 27-Jan-2020
Online since: 2020-09-15T14:30:40Z
Abstract: A limiting factor for oral delivery of macromolecules is low intestinal epithelial permeability. 1-phenylpiperazine (PPZ), 1-(4-methylphenyl) piperazine (1-4-MPPZ), and 1-methyl-4-phenylpiperazine (1-M-4-PPZ) have emerged as potential permeation enhancers (PEs) from a screen carried out by others in Caco-2 monolayers. Here, their efficacy, mechanism of action, and potential for epithelial toxicity were further examined in Caco-2 cells and isolated rat intestinal mucosae. Using high content analysis, PPZ and 1-4-MPPZ decreased mitochondrial membrane potential and increased plasma membrane potential in Caco-2 cells to a greater extent than 1-M-4-PPZ. The Papp of the paracellular marker, [14C]-mannitol, and of the peptide, [3H]-octreotide, were measured across rat colonic mucosae following apical addition of the three piperazines. PPZ and 1-4-MPPZ induced a concentration-dependent decrease in transepithelial electrical resistance (TEER) and an increase in the Papp of [14C]-mannitol without causing histological damage. 1-M-4-PPZ was without effect. The piperazines caused the Krebs-Henseleit buffer pH to become alkaline, which partially attenuated the increase in Papp of [14C]-mannitol caused by PPZ and 1-4-MPPZ. Only addition of 1-4-MPPZ increased the Papp of [3H]-octreotide. Pre-incubation of mucosae with two 5-HT4 receptor antagonists, a loop diuretic, and a myosin-light chain kinase inhibitor reduced the permeation enhancement capacity of PPZ and 1-4-MPP for [14C]-mannitol. 1-4-MPPZ holds most promise as a PE, but intestinal physiology may also be impacted due to multiple mechanisms of action.
Funding Details: European Commission - European Regional Development Fund
Science Foundation Ireland
metadata.dc.description.othersponsorship: CÚRAM Centre for Medical Devices
Type of material: Journal Article
Publisher: Springer
Journal: The AAPS Journal
Volume: 22
Issue: 2
Copyright (published version): 2020 American Association of Pharmaceutical Scientists
Keywords: Intestinal permeation enhancersOral peptide deliveryParacellular delivery1-phenylpiperazine derivativesUssing chambers
DOI: 10.1208/s12248-020-0416-9
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
Veterinary Medicine Research Collection

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