title: Transepithelial transport of morphine and mannitol in Caco-2 cells: the influence of chitosans of different molecular weights and degrees of acetylation.
abstract: The object of this study was to compare the effect of chitosans of different number-average molecular weights (MWs) and degrees of acetylation (F(A)) on transepithelial transport of morphine in Caco-2 cells. Caco-2 monolayers on polycarbonate (PC) membranes (0.5 cm(2)) were incubated with morphine (10 microM) or mannitol (55 microM) for 180 min. Samples for analysis of morphine (LCMSMS) and mannitol (liquid scintillation) were drawn at 45, 90, 120 and 180 min. Transepithelial electrical resistance (TEER) and transmission electron microscopy were used to monitor cell integrity. In controls, morphine transport was half that of mannitol. Chitosans affected the transport of morphine and mannitol similarly. For chitosans with similar F(A) (0.32-0.43) and varying MWs (7-200 kD), transport was increased at MWs of 29 kD or more. Among chitosans of similar MWs (180-300 kD) and varying F(A) (0.01-0.61), those with the highest F(A) (0.61) had the least effect, while chitosans with F(A)/MW 0.01/250 and 0.17/300 promoted the greatest transport. An F(A)/MW of 0.32/200 and 0.43/170 induced a high and stable transport rate. Chitosans may enhance transepithelial transport of morphine by the same mechanism as for mannitol. Chitosans with F(A) of 0.3-0.4 and MW of approx. 200 kD seem favourable in this respect.
authors.affiliation: Pain and Palliation Research Group, Norwegian University of Science and Technology, N-7489 Trondheim, Norway. ola.dale@ntnu.no
authors.forename: Ola
authors.initials: O
authors.lastname: Dale
authors.forename: Turid
authors.initials: T
authors.lastname: Nilsen
authors.forename: Gry
authors.initials: G
authors.lastname: Olaussen
authors.forename: Kåre E
authors.initials: KE
authors.lastname: Tvedt
authors.forename: Frank
authors.initials: F
authors.lastname: Skorpen
authors.forename: Olav
authors.initials: O
authors.lastname: Smidsrød
authors.forename: Kjell M
authors.initials: KM
authors.lastname: Vårum
mesh_terms: D000107:Acetylation; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology*; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008353:Mannitol / Q000493:pharmacokinetics*; D008970:Molecular Weight; D009020:Morphine / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship
chemical_list: D004337:Drug Carriers; D008353:Mannitol; D009020:Morphine; D048271:Chitosan