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

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dc.contributor.authorStuettgen, Vivien-
dc.contributor.authorBrayden, David James- American Association of Pharmaceutical Scientistsen_US
dc.identifier.citationThe AAPS Journalen_US
dc.description.abstractA 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.en_US
dc.description.sponsorshipEuropean Commission - European Regional Development Funden_US
dc.description.sponsorshipScience Foundation Irelanden_US
dc.rightsThis is a post-peer-review, pre-copyedit version of an article published in The AAPS Journal. The final authenticated version is available online at:
dc.subjectIntestinal permeation enhancersen_US
dc.subjectOral peptide deliveryen_US
dc.subjectParacellular deliveryen_US
dc.subject1-phenylpiperazine derivativesen_US
dc.subjectUssing chambersen_US
dc.titleInvestigations of Piperazine Derivatives as Intestinal Permeation Enhancers in Isolated Rat Intestinal Tissue Mucosaeen_US
dc.typeJournal Articleen_US
dc.statusPeer revieweden_US
dc.citation.otherArticle number: 33en_US
dc.neeo.contributorBrayden|David James|aut|-
dc.description.othersponsorshipCÚRAM Centre for Medical Devicesen_US
item.fulltextWith Fulltext-
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Veterinary Medicine Research Collection
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