Abstract
Plasma concentration, distribution, and excretion of [14C]-alendronate were investigated after repeated intravenous administration once a day for 7 days to 7-week old male rats and after a single intravenous administration to 30-week old male rats. Feto-placental transfer in pregnant rats and the transfer into the milk in lactating rats were also investigated.
1. The plasma radioactivity after repeated administration at 0.05 mg/kg of [14C]-alendronate to 7-week old male rats was higher than in single administration. However, there was no difference in the half-lives. The level of radioactivity in noncalcified tissues after repeated administration were also higher than in a single administration, but no accumulation was observed. The maximum level of radioactivity in bones was 6.2-7.5 times higher than in a single dose experiment. The concentration in vertebra was the highest among bones, followed by long bones (femur, tibia, humerus) and calvaria. By the 24th day after final administration, 32.2% of the dosed radioactivity was excreted in the urine and 2.1% in the feces, and the excretion in urine was almost completed within 24 hours. These results suggest that there is no alteration in the disposition of alendronate after repeated administration compared with single administration.
2. The AUC of plasma radioactivity after single administration of 0.05 mg/kg of [14C]-alendronate to 30-week old male rats was 2 times higher than in 7-week old rats. The radioactivity in the liver, kidneys, spleen, and heart was also higher. The maximum level of radioactivity in calvaria in 30-week old rats were similar to those in 7-week rats, but was approximately 50% lower in vertebra and long bones than in 7-week old rats. Therefore, the difference of concentration among bones in 30-week old rats was less than in 7-week old rats. The cumulative urinary excretion at 216 hours after administration to 30-week rats was higher (46% of dose) than in 7-week old rats. On the basis of these results, it is suggested that the increase of concentration of radioactivity in plasma and noncalcified tissues and urinary excretion in 30-week rats is due to the decrease in the bone uptake of alendronate as a consequence of decline of bone turnover.
3. After single administration of [14C]-alendronate at 0.05 mg/kg to female rats on day 19 of pregnancy, the concentration of radioactivity in plasma was similar to that of 7-week old male rats. Radioactivity was not detected in fetus, indicating that feto-placental transfer of alendronate was low.
4. After administration of [14C]-alendronate to female rats 14 days post parturn, the concentration of radioactivity in the milk was higher than in plasma. The transfer of radioactivity into milk was observed.
