We have previously reported the merits of chronopharmacological effect of 1-alpha(OH)
vitamin D3 in aged
stroke-prone spontaneously hypertensive rat (SHRSP), a model of
osteoporosis [Eur. J. Pharmacol. 428 (2001) 283.]. In this study, the chronopharmacological effect of
22-oxacalcitriol, a newly developed active
vitamin D3 analogue with less calcemic activity, was evaluated by a single and repeated dosing of the
drug in aged SHRSP. Animals (7 months old) were kept in rooms with a 12-h light/dark cycle. Single (12.5 microg/kg, i.v.) and repeated (5 microg/kg, i.v. three times a week for 12 weeks) dosing of
22-oxacalcitriol or vehicle was given at either 2 h after lights on (2HALO) or 14 h after lights on (14HALO). The severity of adverse reactions such as the changes of
body weight,
hypercalcemia and
hyperphosphatemia, was significantly mild when the
drug was given at 14HALO. Especially, the increase of serum Ca concentration was not detected at 14HALO trial. Serum concentrations of total (
protein-bound and unbound)
22-oxacalcitriol and
albumin (a major
binding protein of the
drug) of the 2HALO and 14HALO trials did not significantly differ. The decrease of
parathyroid hormone (PTH) concentration was greater in the 14HALO trial while the increase in urinary ratio of Ca to
creatinine was greater in the 2HALO trial. The increase in bone density of both femurs at the end of the study was greater in the 14HALO trial. The suppression of urinary excretion of
deoxypyridinoline, an index of
bone resorption capacity of osteoclast, was greater in the 14HALO trial, which indicates that the efficacy of
22-oxacalcitriol for suppressing
bone resorption might vary with the dosing time. This is the first study to show the dosing-time-dependent changes in the efficacy and toxicity of
22-oxacalcitriol in the animal model of
osteoporosis. Chronopharmacological differences seem to be more prominent than those of other
vitamin D analogues. To use
22-oxacalcitriol at an adequate timing might provide better efficacy and safety than other
vitamin D3 analogues for the treatment of
osteoporosis.