Time of Day Improves Efficacy and Reduces Adverse Reactions of Vitamin D3 in 5/6 Nephrectomized Rat

Time-dependent differences in adverse reactions and efficacy by a repeated administration of 1,25(OH)2 vitamin D3 (vit D, 0.3 microg/Kg/day for 12 weeks) were examined in 5/6 nephrectomized rats under a condition of 12-hour light-dark cycle. The 5/6 nephrectomy increased serum concentrations of phosphate, osteocalcin and PTH, and urinary excretions of phosphate and deoxypyridinoline (DPD) while the maneuver reduced serum Ca concentration and its urinary excretion. Animals with a dosing of the drug at 2 hours after light on (HALO) had more grade of hypercalcemia and hyperphosphatemia than those at 14 HALO. Reduction of serum intact PTH and increase of serum vit D were observed in both groups with a similar extent. Increase of osteocalcin by the drug was greater in 14 HALO trial. Urinary excretion of DPD was not influenced by the treatment. The increase in bone density of femur was greater in 14 HALO than in 2 HALO trials. These results suggest that adverse reactions of vit D were ameliorated and its efficacy was enhanced after the repeated dosing of the drug at 14 HALO. Time-dependent variation in the sensitivity of the drug to osteoblast was involved in the mechanism of these events, while the roles of pharmacokinetic alteration and renal response were small, if any.