ROLE OF CALCIUM IN PLASMA-PROTEIN BINDING AND RENAL HANDLING OF ALENDRONATE IN HYPOCALCEMIC AND HYPERCALCEMIC RATS

Alendronate (4-amino-1-hydroxybutylidine-1,1-bisphosphonate), an antio steolytic agent, is currently under investigation for the treatment of osteoporosis. Earlier studies in animals from this laboratory disclos ed that systemically administered alendronate is rapidly taken up by b one tissues to the extent of 60% to 70% of the dose and excreted by th e kidney, 30% to 40% in 24 hr, and that renal excretion is the only ro ute of elimination. This study was designed to explore the effect of c alcium on plasma protein binding and the renal handling of alendronate . The binding of alendronate to rat plasma was concentration, pH and c alcium dependent. The fraction of unbound drug in rat plasma increased from about 3% to 9% over a drug concentration range of 0.2 to 10 mug/ ml. Supplementation of calcium strongly augmented the binding to serum albumin. The binding of alendronate in plasma increased with increasi ng pH from about 50% at pH 6.6 to 98% at pH 8.6. The effects of pH on the binding of calcium and of alendronate to serum albumin were qualit atively similar. Under steady-state conditions, the binding of alendro nate was substantially lower in hypocalcemic rats but unchanged in hyp ercalcemic rats. Although hypocalcemia caused a significant decrease i n the renal secretion of alendronate, there was no effect on the renal secretion of tetraethylammonium bromide and p-aminohippuric acid. The differential effect of hypocalcemia suggests that calcium may play an important role in the renal handling of alendronate. However, hyperca lcemia resulted in a substantial decrease of renal secretion of all th ree compounds and the decreased renal secretion was associated with a marked decrease in the glomerular filtration rate. These results indic ate that hypercalcemia may cause renal dysfunction.