title: Transintestinal transport mechanisms of 5-aminosalicylic acid (in situ rat intestine perfusion, Caco-2 cells) and Biopharmaceutics Classification System.
abstract: The aim of the study was 1) to estimate permeability of 5-aminosalicylic acid (5-ASA), 2) to categorize 5-ASA according to BCS (Biopharmaceutics Classification System), and 3) to contribute to determination of 5-ASA transintestinal transport and biotransformation mechanisms. The in situ rat intestine perfusion was used as an initial method to study 5-ASA transport. The amount of 5-ASA (released from tablet) transferred into portal circulation reached 5.79 ± 0.24%. During this transport, the intestinal formation of 5-ASA main metabolite (N-ac-5-ASA) occurred. N-ac-5-ASA was found in perfusate both from intestinal lumen and from v. portae. In in vitro Caco-2 monolayers, transport of 5-ASA (10-1000 µmol/l) was studied in apical-basolateral and basolateral-apical direction (iso-pH 7.4 conditions). The transport of total 5-ASA (parent drug plus intracellularly formed N-ac-5-ASA) was linear with time, concentration- and direction-dependent. Higher basolateral-apical (secretory) transport was mainly caused by higher transport of the metabolite (suggesting metabolite efflux transport). Transport of 5-ASA (only parent drug) was saturable (transepithelial carrier-mediated) at low doses, dominated by passive, paracellular process in higher doses which was confirmed by increased 5-ASA transport using Ca2+-free transport medium. The estimated low 5-ASA permeability and its low solubility enable to classify 5-ASA as BCS class IV.
authors.affiliation: Institute of Experimental Biopharmaceutics, Joint Research Centre of the Academy of Sciences of the Czech Republic and PRO.MED.CS Praha a.s., Hradec Králové, Czech Republic. liba.smetanova@seznam.cz.
authors.forename: Libuše
authors.initials: L
authors.lastname: Smetanová
authors.forename: Věra
authors.initials: V
authors.lastname: Stětinová
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kholová
authors.forename: Martin
authors.initials: M
authors.lastname: Kuneš
authors.forename: Milan
authors.initials: M
authors.lastname: Nobilis
authors.forename: Zbyněk
authors.initials: Z
authors.lastname: Svoboda
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Květina
mesh_terms: D000818:Animals; D001711:Biotransformation; D018938:Caco-2 Cells; D002470:Cell Survival; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D019804:Mesalamine / Q000145:classification* / Q000378:metabolism*; D010477:Perfusion; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar
chemical_list: D019804:Mesalamine