Metabolic Fate of 4-amino-1-hydroxybutylidene-1, 1-bisphosphonatee (alendronate) (I) : Plasma Concentration, Distribution and Excretion after Intravenous Administration of Alendronate to Rats

Plasma concentration, distribution, and excretion of [14C]-alendronate after a single intravenous administration were investigated in 7-week old male rats.1. The plasma levels of radioactivity after administration of 0.05, 0.5, 5 and 15 mg/kg of [14C]-alendronate declined rapidly with time at each administered dose. The elimination half-lives were 3-10 minutes (from 5 to 30 min) and 27-60 minutes (from 30 min to 2 hr), and no significant difference in the half-lives was observed between the doses.2. The level of radioactivity in bones and cartilage after administration of 0.05 mg/kg of [14C]-alendronate was higher than in plasma and noncalcified tissues at any time points measured after dosing. The concentration in vertebra was the highest among bones, followed by long bones (femur, tibia, humerus) and calvaria. The autoradiography of the long bones revealed a higher level of radioactivity was observed in metaphysis and epiphysis than in diaphysis, especially in the area adjacent to growth plate. Therefore, it was suggested that alendronate was distributed well to region of bone with high turnover.3. The radioactivity in bones reached a peak concentration at approximately 8 hours after administration and then decreased with a half-life of between 65 and 102 days. Moreover, the half-life of the contents of radioactivity in the long bones and vertebra was between 182 and 242 days. This suggested that decrease in the level of radioactivity in bones was mainly due to increase in bone weight with growth, and substantial elimination of the drug was slow in bones. The uptake of alendronate by bones increased in a dose dependent manner in the range of 0.0515 mg/kg.4. The radioactivity in noncalcified tissues was lower than in bones, and its decrease was rapid.5. By the 9th day after administration of 14C-alendronate at 0.05 mg/kg, 37.5% of the dosed radioactivity was excreted in the urine and 0.3% in the feces. Most of the radioactivity in the urine was excreted within 12 hours after administration.