The effect of zoledronate and pamidronate on the intestinal permeability barrier in vitro and in vivo

The intestinal tolerability profile of the potent bisphosphonate compound zoledronate (CGP 42'446) has been compared with that of pamidronate in 2 preclinical screening models. Despite being 2-3 orders of magnitude more potent than pamidronate as an inhibitor of bone resorption, zoledronate (1-100 mM) was 2-4 fold less potent at disrupting the permeability 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 of 30 mM disrupted the intestinal permeability barrier within 1 h whereas 1 and 10 mM solutions had no effect. Since both EDTA and bisphosphonates are powerful calcium chelators, these changes are most probably due to calcium sequestration and a consequent loosening of tight junctions 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 associated with a corresponding increase in the compound's potential to damage the intestinal mucosa. From these preclinical studies, it is predicted that zoledronate should have a higher therapeutic ratio than pamidronate (anti-resorptive potency in bone versus adverse intestinal effects) in man. (C) 1997 Elsevier Science B.V.