Pf. Augustijns, UPTAKE AND TRANSPORT CHARACTERISTICS OF CHLOROQUINE IN AN IN-VITRO CELL-CULTURE SYSTEM OF THE INTESTINAL-MUCOSA, CACO-2, Journal of Pharmacy and Pharmacology, 48(3), 1996, pp. 277-280
The transepithelial transport and uptake of chloroquine were studied i
n cultured human intestinal Caco-2 cell layers, to investigate whether
a specific mechanism facilitates the flux of chloroquine. Due to ioni
zation of chloroquine at the pH of the intestinal lumen, the fraction
of the neutral form, which is required for partitioning into biologica
l membranes, is very low, while oral bioavailability has been reported
to be nearly complete. Several observations, such as concentration-de
pendent uptake and temperature-dependent transepithelial flux, suggest
the presence of carrier mediated transport. However, alternative mech
anisms may be invoked to explain these observations. It is suggested t
hat concentration dependence can originate from ion-trapping in acidic
compartments of the cell or non-specific binding to cell components,
while temperature-dependent transport can, at least partly, be explain
ed by the temperature dependence of the acid dissociation constants of
chloroquine. No differences were observed in the transepithelial flux
of the enantiomers of chloroquine. pH-dependent uptake as well as pH-
dependent transepithelial transport suggest that the translocation of
chloroquine occurs according to the fraction of neutral molecules. Fro
m the data obtained in this study, it is concluded that chloroquine cr
osses the gastrointestinal barrier by passive diffusion. The extensive
area of the gastrointestinal tract probably compensates for the low f
raction of the neutral molecule. An interesting finding of this study
was the concentration-dependent increase in transepithelial electrical
resistance across monolayers incubated with chloroquine at the apical
side.