Pl. Nicklin et al., DEVELOPMENT OF A MINIMUM-CALCIUM CACO-2 MONOLAYER MODEL - CALCIUM ANDMAGNESIUM-IONS RETARD THE TRANSPORT OF PAMIDRONATE, International journal of pharmaceutics, 123(2), 1995, pp. 187-197
The oral absorption of some drug molecules (e.g., tetracyclines and qu
inolones) is limited by complexation with di- and trivalent metal cati
ons in the gastrointestinal tract. Progress in the understanding of th
ese absorption-limiting interactions has been restricted in the absenc
e of a suitable in vitro model. To address this, a modification of the
conventional Caco-2 transport model has been developed which has a ca
lcium-free apical donor solution and a basolateral receiver solution c
ontaining the minimum calcium concentration required to maintain monol
ayer integrity (100 mu M). The minimum-calcium model is proposed to be
a useful universal model for studying the influence of metal cations
on the transepithelial transport of drug molecules. The influence of c
alcium and magnesium ions on the absorption of pamidronate was evaluat
ed by comparing its transport across the conventional and minimum-calc
ium Caco-2 models. In the conventional Caco-2 model, the ratio of mann
itol/pamidronate flux was 5:1, whereas in the minimum-calcium model th
is ratio was reduced to 3:1. The elevated transepithelial transport ra
te for pamidronate in the minimum-calcium model cannot be explained by
minor changes in the permeability of Caco-2 monolayers. It was conclu
ded that calcium and magnesium ions retard the apical-to-basolateral f
lux of pamidronate across Caco-2 monolayers.