Renal transport of bisphosphonates: accumulation by renal cortical slices enhanced by calcium phosphate ions.

Bisphosphonates have been recognized as useful therapeutic agents in metabolic bone disease. Earlier studies showed a net renal secretion of 1-hydroxy-ethylidene-1,1-bisphosphonate (HEBP). They suggested a renal cellular uptake of this compound. We further studied this concept by investigating the uptake in vitro of 14C-HEBP by rat renal cortex slices. HEBP was accumulated against a concentration gradient, a process that was dependent on time, temperature, and substrate concentration. Unlike that of 3H-p-aminohippurate, the uptake was not affected by change in medium Na+ or glucose and acetate concentration, or by anoxia and various metabolic inhibitors. It was, however, markedly increased by raising the medium calcium and inorganic phosphate concentration. Equilibrium dialysis with renal cortex homogenates suggests that HEBP binds to a cytosolic macromolecule through a process that exhibits saturability and calcium dependency. In conclusion, the results suggest that the bisphosphonate HEBP can penetrate kidney cells by a process that does not appear to be energy dependent, but is markedly influenced by the extracellular calcium-phosphate concentration.