THE TRANSPORT OF 2 IRON CHELATORS, DESFERRIOXAMINE B AND L1, ACROSS CACO-2 MONOLAYERS

The transport of two iron chelators, desferrioxamine B (DFO) and L1 (1 ,2-dimethyl-3 hydroxypyridin-4-one) has been studied in vitro using th e human adenocarcinoma cell line, Caco-2. The transport of DFO and L1 has also been compared with that of their iron-bound complexes, ferrio xamine (FO) and L1(3)-Fe, respectively. We report an apparent permeabi lity coefficient (P-app) value for DFO of 0.170x10(-7) +/-0.080 cm s(- 1). The P-app value of L1 was 1.297 x 10(-5) +/-0.133 cm s(-1). The P- app values of their iron bound complexes FO and L1(3)-Fe are 0.230 x 1 0(-7) +/-0.065 cm s(-1) and 2.356 x 10(-6) +/-0.365 cm s(-1), respecti vely. 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 DF O into the Caco-2 cells was 1.49+/-0.09x10(-3) mmol per filter. The va lues for total uptake after 60 min for L1 and L1(3)-Fe were 0.37+/-0.0 3 nmol per filter and 0.04+/-0.01 nmol per filter, respectively. Our r esults indicate that the poor oral bioavailability of DFO can be attri buted to the tow 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 th e two molecules account for LI being better orally absorbed than DFO.