Transport kinetics of iron chelators and their chelates in Caco-2 cells.
OBJECTIVE
Caco-2 monolayers were used to contrast the bidirectional transport of iron chelators and their chelates and to estimate fundamental kinetics associated with their intestinal absorption.


METHODS
Bidirectional transport was studied at 37 degrees C and pH 7.4 using 500-microM concentrations. Monolayer integrity was tested via transepithelial electrical resistance and sodium fluorescein permeability. Apical and basolateral analysis provided mass balance evidence. Apparent permeability coefficient (P(app)) served to rank and compare molecules and estimate in vivo bioavailability. Model-dependent rate constants defined cellular influx and efflux.


RESULTS
1) P(app) ranked in decreasing order for chelators from directional transport studies were CP363 > deferiprone> ICL670 > CP502 > deferoxamine (DFO). 2) Fe(CP502)(3), Fe(ICL670)(2), and FeDFO were not measurable in receiving chambers, whereas Fe(deferiprone)(3) and Fe(CP363)(3) were detected in both directions. 3) CP363 was transported significantly faster from the basolateral to the apical direction than the converse. 4) Mass balance of donor and receiver chambers gave approximately 100% recovery in all cases. 5) Kinetic analysis supports the view that the Caco-2 chelator efflux constants are generally greater than their influx constants.


CONCLUSIONS
Caco-2 cells are useful in screening iron chelators and chelates and estimating bioavailabilities. Structure and distribution coefficients partially predict passive transport through Caco-2 monolayers.
Huang
Xi-Ping
XP
Leslie Dan Faculty of Pharmacy, University of Toronto, 19 Russell St., Toronto, Ontario, Canada, M5S 2S2.
Spino
M
M
Thiessen
J J
JJ
D000465:Algorithms; D001682:Biological Availability; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D017097:Electric Impedance; D019793:Fluorescein; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000378:metabolism*; D007700:Kinetics; D013329:Structure-Activity Relationship
D007502:Iron Chelating Agents; D007501:Iron; D019793:Fluorescein