Pharmaceutical Research

, Volume 34, Issue 6, pp 1320–1329

Structure-Function Analysis of Phenylpiperazine Derivatives as Intestinal Permeation Enhancers

  • Katherine C. Fein
  • Nicholas G. Lamson
  • Kathryn A. Whitehead
Research Paper

DOI: 10.1007/s11095-017-2149-8

Cite this article as:
Fein, K.C., Lamson, N.G. & Whitehead, K.A. Pharm Res (2017) 34: 1320. doi:10.1007/s11095-017-2149-8

Abstract

Purpose

A 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.

Methods

The 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.

Results

Of 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.

Conclusions

Several potent derivatives, including 1-methyl-4-phenylpiperazine and 1-(4-methylphenyl)piperazine, displayed lower toxicity than 1-phenylpiperazine, suggesting promise in future applications.

Key Words

1-phenylpiperazine Caco-2 oral delivery permeation enhancer piperazine derivatives 

Abbreviations

BSA

Bovine serum albumin

BSM

Basal seeding medium

DMEM

Dulbecco’s Modified Eagle’s Medium

EDM

Enterocyte differentiation medium

EP

Enhancement potential

MTT

Methyl thiazole tetrazolium

OP

Overall potential

TEER

Trans-epithelial electrical resistance

TP

Toxicity potential

Supplementary material

11095_2017_2149_MOESM1_ESM.docx (22 kb)
Table S1(DOCX 21 kb)
11095_2017_2149_MOESM2_ESM.docx (86 kb)
Figure S1(DOCX 86 kb)

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Katherine C. Fein
    • 1
  • Nicholas G. Lamson
    • 1
  • Kathryn A. Whitehead
    • 1
    • 2
  1. 1.Department of Chemical EngineeringCarnegie Mellon UniversityPittsburghUSA
  2. 2.Department of Biomedical EngineeringPittsburghUSA

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