Chronopharmacology of oxacalcitriol in rat model of osteoporosis.
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.
Tsuruoka
Shuichi
S
Department of Pharmacology, Division of Clinical Pharmacology, Jichi Medical School, 3311 Yakushiji, Minamikawachi, Kawachi, Tochigi 329-0498, Japan. tsuru@jichi.ac.jp
Wakaumi
Michis
M
Yamamoto
Hisashi
H
Fujimura
Akio
A
D015502:Absorptiometry, Photon; D000596:Amino Acids / Q000652:urine; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D002118:Calcium / Q000097:blood / Q000652:urine; D003404:Creatinine / Q000652:urine; D004305:Dose-Response Relationship, Drug; D008297:Male; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000188:drug therapy*; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood; D051381:Rats; D011918:Rats, Inbred SHR; D012709:Serum Albumin / Q000378:metabolism; D013997:Time Factors
D000596:Amino Acids; D010281:Parathyroid Hormone; D012709:Serum Albumin; D010758:Phosphorus; C036020:deoxypyridinoline; D003404:Creatinine; D002117:Calcitriol; C051883:maxacalcitol; D002118:Calcium