DEVELOPMENT OF A MINIMUM-CALCIUM CACO-2 MONOLAYER MODEL - CALCIUM ANDMAGNESIUM-IONS RETARD THE TRANSPORT OF PAMIDRONATE

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.