THE PHARMACOKINETICS AND DISTRIBUTION OF PAMIDRONATE FOR A RANGE OF DOSES IN THE MOUSE

The pharmacokinetics of the bisphosphonate drug pamidronate (APD, 3-amino-1-hydroxypropylidene-1,1-bisphosphonate) have been investigated in the mouse by using 14C-APD and following the tissue concentrations for up to 90 days postdose. The accumulation of APD in bone was the highest of all tissues and was linear with increasing dose up to the maximum dose employed (30 mg/kg), which is indicative of the uptake process being a simple chemical phenomenon. Despite the known effects of APD on bone turnover rates and osteoclast activity, the dose appeared to have no significant influence on the biological half-life of APD in bone which was found to be 90-140 days. A high dose of APD (5 mg/kg) appeared to prolong its uptake phase by bone, however, a net movement of APD from the soft tissues is the likely explanation for this finding. The concentrations of APD in the soft tissues investigated (liver, spleen, kidney, lung, and muscle) declined in a biphasic manner, initially in parallel with the fall in the plasma concentration and followed by a gradual fall in APD's concentration in the soft tissues due to renal elimination and a redistribution favoring the calcified tissues. The liver and spleen contained higher concentrations of APD relative to the other soft tissues. The 0-24 hour renal excretion of APD was found to fall with increasing dose above 2.5 mg/kg; this may be due to either nephrotoxicity or increased uptake by soft tissues. For doses over 20 mg/kg, there was some evidence of nephrotoxicity. The data from these studies have been used to formulate a simple physiological model for APD disposition.