Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.24.64 (
MPP
)
1,876
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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 P
app
of the paracellular marker, [
14
C]-mannitol, and of the peptide, [
3
H]-octreotide, was 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 P
app
of [
14
C]-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 P
app
of [
14
C]-mannitol caused by PPZ and 1-4-MPPZ. Only addition of 1-4-MPPZ increased the P
app
of [
3
H]-octreotide. Pre-incubation of mucosae with two 5-HT
4
receptor antagonists, a loop diuretic and a
myosin light chain kinase
inhibitor, reduced the permeation enhancement capacity of PPZ and 1-4-
MPP
for [
14
C]-mannitol. 1-4-MPPZ holds most promise as a PE, but intestinal physiology may also be impacted due to multiple mechanisms of action.
...
PMID:Investigations of Piperazine Derivatives as Intestinal Permeation Enhancers in Isolated Rat Intestinal Tissue Mucosae. 3198 62
