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.
Summary:We report the results of two consecutive randomized studies in the treatment of malignant hypercalcaemia with intravenous pamidronate. Overall normocalcaemia was achieved in greater than 90% of patients and a single infusion of60 mg pamidronate given over 2 hours was as effective in restoring normocalcaemia as infusions given over 4, 8 or 24 hours. Similarly duration of normocalcaemia after treatment with pamidronate and the control of the symptoms of hypercalcaemia were independent of infusion rate. Study of the pharmacokinetics of pamidronate in the treatment ofhypercalcaemia show this drug to have a very high clearance due to calcified tissue retention and renal excretion. The initial half life of the drug in plasma is very short and most of the drug is cleared before distribution equilibrium is achieved. Short infusions ofpamidronate are as safe and effective as infusions given over a longer time and are therefore to be preferred because of their greater convenience.
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