Relationship between structure and permeability of dipeptide derivatives containing tryptophan and related compounds across human intestinal epithelial (Caco-2) cells.
The permeability of dipeptide derivatives containing tryptophans and indole derivatives through Caco-2 cells was used as an in vitro intestinal absorption model in order to clarify structural factors which influence their intestinal epithelial permeation and metabolism. Most peptide derivatives were hydrolysed not only by the cytosolic enzymes in Caco-2 cells during permeation but also by enzymes released to the apical solution before cell permeation. The N-terminal blocked dipeptides were more resistant to hydrolases expressed in the Caco-2 cells and indole derivatives were not entirely degraded. Based on compound concentration dependency and comparison of permeability coefficients in apical-to-basolateral and basolateral-to-apical directions, the main absorption mechanism of compounds were determined. Compounds were then classified into three groups; (1) passively transported compounds, (2) actively transported compounds and (3) compounds excreted by P-glycoprotein.
Ano
Rieko
R
Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
Kimura
Yukitaka
Y
Urakami
Machiko
M
Shima
Motohiro
M
Matsuno
Ryuichi
R
Ueno
Tamio
T
Akamatsu
Miki
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D026905:Amino Acid Transport Systems / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004151:Dipeptides / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000737:chemistry* / Q000493:pharmacokinetics*; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D026905:Amino Acid Transport Systems; D004151:Dipeptides; D014364:Tryptophan; D014700:Verapamil