Dosing time-dependent variation in the hypocalcemic effect of calcitonin in rat

Dosing time-dependent variation in the hypocalcemic effect of salmon calcitonin was examined in rats under a 12-h light-dark cycle. In both a single-dosing study with normal rats and a repeated-dosing study with hypercalcemic rats (induced by chronic vitamin-D dosing), we consistently observed that the hypocalcemic effect of calcitonin was greater when the drug was given at 14 h after lights on than that at 2 h after lights on. The reduction in urinary deoxypyridinoline excretion, a marker of bone resorption, was also greater when calcitonin was given at 14 h after lights on. Urinary excretion of Ca was not affected by the drug. Pharmacokinetic profiles of calcitonin after a single dosing did not differ between the two trials. These results indicate that the hypocalcemic effect of calcitonin is greater after dosing in the early dark phase (14 h after lights on) than after dosing in the early light phase (2 h after lights on). A time-dependent variation in the sensitivity to the drug of osteoclasts, but not renal tissues, may be involved in the mechanism of this event.