Importance of intermolecular interaction on the improvement of intestinal therapeutic peptide/protein absorption using cell-penetrating peptides.
Our previous reports showed that the absorption of therapeutic peptides and proteins was significantly improved by coadministration of cell-penetrating peptides (CPPs) as the physical mixture. However, the mechanisms for this improvement are not clear. In the present study, we verified the hypothesis that the electrostatic interaction between drug and CPP is related to the enhancing effect of the CPP on the intestinal absorption of therapeutic peptides and proteins. In this study, the intermolecular binding was analyzed by surface plasmon resonance (SPR)-based binding assay, and the effect of CPPs on the intestinal absorption of peptide drugs was examined by in situ absorption study using a rat intestinal loop. Among the 16 peptide drugs possessing different isoelectric points, it was observed that only gastrin, insulin and glucagon-like peptide-1 (GLP-1) bound to D-R8 (D-form arginine octamer, a typical CPP), and subsequently their intestinal absorption increased by coadministration of D-R8. In contrast, the intestinal absorption of other peptide drugs that did not bind to D-R8 was not affected in the presence of D-R8. Thus, this study suggests that intermolecular binding between drug and CPP is an important factor governing the enhancing effect of the CPP on the intestinal absorption of therapeutic peptides and proteins.
Kamei
Noriyasu
N
Department of Pharmaceutics, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan.
Morishita
Mariko
M
Takayama
Kozo
K
D000595:Amino Acid Sequence; D000818:Animals; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007082:Ileum / Q000378:metabolism; D054795:Incretins / Q000378:metabolism / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D009842:Oligopeptides / Q000378:metabolism* / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism* / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D020349:Surface Plasmon Resonance
D054795:Incretins; D009842:Oligopeptides; D010455:Peptides; C500307:octa-arginine peptide; D052216:Glucagon-Like Peptide 1