title: Evaluation of absorption enhancement for a potent cyclopeptidic alpha(nu)beta(3)-antagonist in a human intestinal cell line (Caco-2).
abstract: Different absorption enhancing principles for a potent cyclopeptidic alpha(nu)beta(3)-antagonist (EMD 121974) were investigated in monolayers of a human intestinal cell line (Caco-2). Transepithelial transport was quantitated by reversed-phase high-performance liquid chromatography. Cytotoxic effects were characterized by determination of transepithelial electrical resistances (TEERs), propidium iodide (PI)-influx, FITC-phalloidin staining and the release of cytosolic lactate dehydrogenase (LDH). Medium chain fatty acids (MCFAs, NaC10, NaC12) and taurocholate (NaTC) were the most efficient enhancers of cyclopeptide and FITC-dextran 4400 permeability coefficients, displaying different time profiles of activity. Whereas NaTC (15 mM) showed almost a constant permeation enhancing effect from 20 min up to 120 min (ca. 12-fold), MCFA absorption enhancement was markedly dependent on incubation time (NaC10, 20 min: 1.2-fold, 120 min: 17-fold; NaC12, 20 min: 4.3-fold, 120 min: 13-fold). All cytotoxicity assays demonstrated that MCFAs were significantly more cytotoxic than NaTC. Ion pairing with hydrophobic amino acids and heptane sulfonate distinctly increased octanol-buffer partition coefficients of the cationic cyclopeptide but did not enhance its transepithelial permeability. Nanoparticles as well as beta-cyclodextrin neither affected integrity of the cells nor transport properties of the cyclopeptide. In summary, significant absorption enhancement was only observed with NaTC or MCFAs. Increase in permeability coefficients using NaTC occurred rapidly with acceptable cytotoxicities and merits further investigations.
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Philipps University of Marburg, Ketzerbach 63, D-35032, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Kamm
authors.forename: A
authors.initials: A
authors.lastname: Jonczyk
authors.forename: T
authors.initials: T
authors.lastname: Jung
authors.forename: G
authors.initials: G
authors.lastname: Luckenbach
authors.forename: P
authors.initials: P
authors.lastname: Raddatz
authors.forename: T
authors.initials: T
authors.lastname: Kissel
mesh_terms: D001692:Biological Transport; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003652:Decanoic Acids / Q000494:pharmacology; D004134:Dimyristoylphosphatidylcholine / Q000494:pharmacology; D004553:Electric Conductivity; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007850:Lauric Acids / Q000494:pharmacology; D008823:Micelles; D008863:Microspheres; D000442:Octanols / Q000737:chemistry; D010456:Peptides, Cyclic / Q000493:pharmacokinetics*; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D012910:Snake Venoms; D012995:Solubility; D013656:Taurocholic Acid / Q000494:pharmacology
chemical_list: D003652:Decanoic Acids; D007850:Lauric Acids; D008823:Micelles; D000442:Octanols; D010456:Peptides, Cyclic; D019030:Receptors, Vitronectin; D012910:Snake Venoms; C030358:lauric acid; C422910:Cilengitide; C031071:decanoic acid; D013656:Taurocholic Acid; D007770:L-Lactate Dehydrogenase; D004134:Dimyristoylphosphatidylcholine