THE EFFECT OF ZOLEDRONATE AND PAMIDRONATE ON THE INTESTINAL PERMEABILITY BARRIER IN-VITRO AND IN-VIVO

The intestinal tolerability profile of the potent bisphosphonate compo und zoledronate (CGP 42'446) has been compared with that of pamidronat e in 2 preclinical screening models. Despite being 2-3 orders of magni tude more potent than pamidronate as an inhibitor of bone resorption, zoledronate (1-100 mM) was 2-4 fold less potent at disrupting the perm eability barrier of monolayers of an intestinal epithelial cell line ( Caco-2) in vitro. In an acute in vivo rat model, luminal perfusion of ileal loops with zoledronate, pamidronate or EDTA at a concentration o f 30 mM disrupted the intestinal permeability barrier within 1 h where as 1 and 10 mM solutions had no effect. Since both EDTA and bisphospho nates are powerful calcium chelators, these changes are most probably due to calcium sequestration and a consequent loosening of tight junct ions between the intestinal epithelial cells rather than to a specific pharmacological action. Thus, in comparison to pamidronate, the high potency of zoledronate as an inhibitor of bone resorption is not assoc iated with a corresponding increase in the compound's potential to dam age the intestinal mucosa. From these preclinical studies, it is predi cted that zoledronate should have a higher therapeutic ratio than pami dronate (anti-resorptive potency in bone versus adverse intestinal eff ects) in man. (C) 1997 Elsevier Science B.V.