A claudin-4 modulator enhances the mucosal absorption of a biologically active peptide

Biochem Pharmacol. 2010 May 15;79(10):1437-44. doi: 10.1016/j.bcp.2010.01.010. Epub 2010 Jan 21.

Abstract

Biologics, such as peptides, proteins and nucleic acids, are emerging pharmaceuticals. Passage across the epithelium is the first step in the absorption of biologics. Tight junctions (TJ) function as seals between adjacent epithelial cells, preventing free movement of solutes across the epithelium. We previously found that modulation of a key TJ component, claudin-4, is a potent method to enhance jejunal absorption when we used dextran as a model drug and the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) as a claudin-4 modulator. Here, we investigated whether the claudin-4 modulator enhances jejunal, nasal and pulmonary absorption of a biologics human parathyroid hormone derivative, hPTH(1-34). The claudin-4 modulator enhanced nasal but not jejunal and pulmonary absorption of hPTH(1-34). C-CPE is hydrophobic with low solubility of less than 0.3mg/ml, but deletion of 10 amino acids at the N-terminal of C-CPE increased its solubility by 30-fold. Moreover, the N-terminal truncated C-CPE bound to claudin-4, modulated the TJ-barrier and enhanced jejunal absorption of dextran. The N-terminal-truncated C-CPE also enhanced jejunal and pulmonary absorption of hPTH(1-34). This report is the first to indicate that a claudin-4 modulator may be a promising enhancer of the jejunal, pulmonary and nasal absorption of a peptide drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorption / drug effects
  • Absorption / physiology
  • Animals
  • Caco-2 Cells
  • Claudin-4
  • Dextrans / metabolism
  • Enterotoxins / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Epithelium / drug effects
  • Epithelium / physiology
  • Humans
  • Intestinal Absorption / drug effects*
  • Intestinal Absorption / physiology
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / physiology
  • Jejunum / drug effects
  • Jejunum / physiology
  • Male
  • Membrane Proteins / drug effects*
  • Membrane Proteins / physiology
  • Nasal Mucosa / drug effects*
  • Nasal Mucosa / physiology
  • Peptides / metabolism
  • Rats
  • Rats, Wistar
  • Respiratory Mucosa / drug effects*
  • Respiratory Mucosa / physiology
  • Surface Plasmon Resonance
  • Teriparatide / metabolism
  • Tight Junctions / drug effects

Substances

  • CLDN4 protein, human
  • Claudin-4
  • Dextrans
  • Enterotoxins
  • Membrane Proteins
  • Peptides
  • enterotoxin, Clostridium
  • Teriparatide