title: The transport of two iron chelators, desferrioxamine B and L1, across Caco-2 monolayers.
abstract: The transport of two iron chelators, desferrioxamine B (DFO) and L1 (1,2-dimethyl-3 hydroxypyridin-4-one) has been studied in vitro using the human adenocarcinoma cell line, Caco-2. The transport of DFO and L1 has also been compared with that of their iron-bound complexes, ferrioxamine (FO) and L1(3)-Fe, respectively. We report an apparent permeability coefficient (Papp) value for DFO of 0.170 x 10(-7) +/- 0.080 cm s-1. The Papp value of L1 was 1.297 x 10(-5) +/- 0.133 cm s-1. The Papp values of their iron bound complexes FO and L1(3)-Fe are 0.230 x 10(-7) +/- 0.065 cm s-1 and 2.356 x 10(-6) +/- 0.365 cm s-1, respectively. We have shown that the transport of DFO and FO is similar in the Caco-2 cell system. The transport of L1, however, is greatly reduced when complexed to iron. The value for total uptake after 60 min for DFO into the Caco-2 cells was 1.49 +/- 0.09 x 10(-3) nmol per filter. The values for total uptake after 60 min for L1 and L1(3)-Fe were 0.37 +/- 0.03 nmol per filter and 0.04 +/- 0.01 nmol per filter, respectively. Our results indicate that the poor oral bioavailability of DFO can be attributed to the low epithelial permeability of the molecule coupled with its size (mol wt 656). In contrast, the oral bioavailability observed with L1 is due to the high lipophilicity and low molecular weight (mol wt 139) of the molecule. We believe that these differences between the two molecules account for L1 being better orally absorbed than DFO.
authors.affiliation: Drug Preformulation and Delivery, Ciba Pharmaceuticals, Horsham, U.K.
authors.forename: K O
authors.initials: KO
authors.lastname: Hamilton
authors.forename: L
authors.initials: L
authors.lastname: Stallibrass
authors.forename: I
authors.initials: I
authors.lastname: Hassan
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
authors.forename: C
authors.initials: C
authors.lastname: Halleux
authors.forename: M
authors.initials: M
authors.lastname: Mackay
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D000077543:Deferiprone; D003676:Deferoxamine / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005290:Ferric Compounds / Q000493:pharmacokinetics; D006801:Humans; D007501:Iron / Q000493:pharmacokinetics; D007502:Iron Chelating Agents / Q000493:pharmacokinetics; D008353:Mannitol / Q000493:pharmacokinetics; D011728:Pyridones / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured
chemical_list: D005290:Ferric Compounds; D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone; D008353:Mannitol; C002577:ferrioxamine B; D007501:Iron; D003676:Deferoxamine