Renal secretion of diphosphonates in rats

Diphosphonates, characterized by a P--C--P bond, are relatively new experimental drugs used for the treatment of myositis ossificans, dental calculus, nephrolithiasis and Paget's disease. These compounds are not metabolized and the fraction which is not taken up by the skeleton is excreted unchanged in the urine. In the present study, the renal clearances of two 14C-labelled diphosphonates, disodium ethane-1-hydroxy-1,1-diphosphonate (CEHDP) and disodium dichloromethylene diphosphonate (CC12MDP) have been measured in conscious rats. The clearances have been found to be higher than the glomerular filtration rate (GFR), Cdiphosphonate/GFR being about 1.5. This observation indicates net tubular secretion of both drugs. High plasma concentration of EHDP or Cl2MDP significantly depressed CEHDP, whereas CEHDP was not influenced by varying urine pH, by infusing NH4Cl or NaHCO3, or by simultaneous administration of high doses of para-aminohippurate (PAH), probenecid, N-methylnicotinamide or Ca-EDTA. High plasma concentration of inorganic phosphate depressed CEHDP and also depressed the in vitro ultrafiltrability of EHDP. In conclusion, these results provide evidence of an active renal transport of diphosphonates which appears distinct from the mechanisms handling organic acids, organic bases and EDTA in the rat kidney.