Relationship between structure and permeability of dipeptide derivatives containing tryptophan and related compounds across human intestinal epithelial (Caco-2) cells

• Published in: Bioorganic & medicinal chemistry 2004-01, Vol.12 (1), p.249-255
• Main Authors: Ano, Rieko, Kimura, Yukitaka, Urakami, Machiko, Shima, Motohiro, Matsuno, Ryuichi, Ueno, Tamio, Akamatsu, Miki
• Format: Article
• Language: English
• Subjects: Amino Acid Transport Systems - pharmacokinetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; Biological and medical sciences; Biological Transport - drug effects; Caco-2; Caco-2 Cells; Cell Membrane Permeability - drug effects; Dipeptide derivatives; Dipeptides - chemistry; Dipeptides - pharmacokinetics; General pharmacology; Humans; Hydrogen-Ion Concentration; Indole compounds; Intestinal Mucosa - cytology; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Medical sciences; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Structure-Activity Relationship; Structure–permeability relationships; Tryptophan - chemistry; Tryptophan - pharmacokinetics; Verapamil - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2003.10.001

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. 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.