Effects of dose, sex, and age on the disposition of alendronate, a potent antiosteolytic bisphosphonate, in rats.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of a variety of bone disorders. Earlier studies from this laboratory have demonstrated that systemically administered drug was rapidly taken up by bone tissue or excreted by the kidneys. Approximately 60 to 70% of the dose was taken up by the bone, and 30 to 40% was excreted in the urine. The purpose of this study was to determine the effects of dose, sex, and age on the disposition kinetics of alendronate using rats as an animal model. No evidence of saturation of drug uptake by the bone was observed in young rats when small, repetitive doses of alendronate were administered every 3 days for 21 days (total 35 mg/kg iv). However, less than proportional uptake by the bone was observed in young rats when single iv doses exceeded 10 mg/kg. Overall, a 500-fold increase in dose resulted in a 350-fold increase in drug concentration in bone. Nonlinear uptake of alendronate by bone was accompanied by simultaneous accumulation in noncalcified tissues at high doses. Less than 1% of the dose was found in noncalcified tissues at 24 hr after low doses (1 mg/kg iv), and 25% after high doses (30 mg/kg iv). Following iv administration, uptake of alendronate by the bone was lower in senescent rats than in young rats by a factor of 2 to 3. Bone uptake was lower in female rats than in male rats by about 30 to 40%, but this sex difference was only observed at low doses and in young rats.