Structure-Function Analysis of Phenylpiperazine Derivatives as Intestinal Permeation Enhancers

doi:10.1007/s11095-017-2149-8

Paper

Structure-Function Analysis of Phenylpiperazine Derivatives as Intestinal Permeation Enhancers

Published Apr 3, 2017 · Katherine C. Fein, Nicholas G. Lamson, K. Whitehead

Pharmaceutical Research

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Abstract

PurposeA major obstacle preventing oral administration of macromolecular therapeutics is poor absorption across the intestinal epithelium into the bloodstream. One strategy to improve transport across this barrier is the use of chemical permeation enhancers. Several molecular families with permeation enhancing potential have been identified previously, including piperazines. In particular, 1-phenylpiperazine has been shown to enhance transepithelial transport with minimal cytotoxicity compared to similarly effective molecules. To better understand how the chemistry of 1-phenylpiperazine affects its utility as an intestinal permeation enhancer, this study examined a small library of 13 derivatives of 1-phenylpiperazine.MethodsThe efficacy and cytotoxicity of 13 phenylpiperazine compounds were assessed in a Caco-2 model of the intestinal epithelium. Efficacy was measured using the paracellular diffusion marker calcein as well as by immunostaining and confocal imaging of Caco-2 monolayers.ResultsOf the 13 derivatives, two enhanced the permeability of the fluorescent marker calcein over 100-fold. It was found that hydroxyl or primary amine substitutions on the phenyl ring significantly increased toxicity, while aliphatic substitutions resulted in efficacy and toxicity profiles comparable to 1-phenylpiperazine.ConclusionsSeveral potent derivatives, including 1-methyl-4-phenylpiperazine and 1-(4-methylphenyl)piperazine, displayed lower toxicity than 1-phenylpiperazine, suggesting promise in future applications.

In Vitro Study

Study Snapshot

Phenylpiperazine derivatives, such as 1-methyl-4-phenylpiperazine and 1-(4-methylphenyl)piperazine, show potential as intestinal permeation enhancers with lower toxicity than 1-phenylpiperazine.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Structure-Function Analysis of Phenylpiperazine Derivatives as Intestinal Permeation Enhancers

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Citations

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Sweet Cherry Extract as Permeation Enhancer of Tyrosine Kinase Inhibitors: A Promising Prospective for Future Oral Anticancer Therapies

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Oral insulin delivery has potential benefits, including patient compliance and reduced costs, but currently faces barriers in the gastrointestinal tract and has not been commercialized.

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Phenylpiperazine-modified dendrimers efficiently deliver proteins into cells through caveolar endocytosis, enabling rapid protein release and high permeability in three-dimensional cell spheroids.

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