title: Structure-activity relationships for enhancement of paracellular permeability by 2-alkoxy-3-alkylamidopropylphosphocholines across Caco-2 cell monolayers.
abstract: The oral route is the preferred route of delivery for a large number of drug molecules. However, the intestinal epithelium presents a formidable barrier for delivery of drugs into systemic circulation. Phospholipids are among compounds that enhance the absorption of drugs across the intestinal epithelium. In this paper, we describe structure-activity relationships for phospholipid derivatives as enhancers of paracellular permeability across Caco-2 cell monolayers. In a series of 2-alkoxy-3-alkylamidopropylphosphocholine derivatives, compounds with a long chain at C-3 (R3) and short chain at C-2 (R2) were potent in causing a decrease in transepithelial electrical resistance (TEER) and an increase in mannitol transport, but also showed significant cytotoxicity. Compounds with 9-11 carbons at C-3 and 6-10 carbons at C-2 provided good separation (up to 2.7-fold) between activity and cytotoxicity. Notably, a good correlation (r2 = 0.93) was observed between EC(50) (TEER) [concentration that caused a drop in TEER to 50% of its control (untreated) value] and EC10x (mannitol) [concentration that caused 10-fold increase in mannitol transport over the control (untreated) value], confirming that a decrease in TEER is associated with enhanced permeability of the hydrophilic compounds across Caco-2 cell monolayers. Compounds with medium to long carbon chains at C-2 and C-3, and the total carbons in the alkyl chains > 20, showed poor activity and no cytotoxicity.
authors.affiliation: Division of Drug Delivery and Disposition, and Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA.
authors.forename: D Z
authors.initials: DZ
authors.lastname: Liu
authors.forename: S L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: L S
authors.initials: LS
authors.lastname: Kucera
authors.forename: K S
authors.initials: KS
authors.lastname: Ishaq
authors.forename: D R
authors.initials: DR
authors.lastname: Thakker
mesh_terms: D018938:Caco-2 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004492:Edetic Acid / Q000494:pharmacology; D017097:Electric Impedance; D006801:Humans; D008353:Mannitol / Q000493:pharmacokinetics; D010713:Phosphatidylcholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
chemical_list: D010713:Phosphatidylcholines; D008353:Mannitol; D004492:Edetic Acid