title: Chronopharmacology of oxacalcitriol in 5/6 nephrectomized rats.
abstract: We previously reported on the merits of the chronopharmacological effects of 1,25(OH) 2 vitaminD3 in 5/6 nephrectomized rats (Tsuruoka et al, Life Scineces 2002; 71: 1809-1820). In this study, the chronopharmacological effect of 22-oxacalcitriol (OCT), a newly developed active vitaminD3 analogue with less calcemic activity, was evaluated by a single and repeated dosing of the drug. The 5/6 nephrectomized animals 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 OCT or vehicle was given at either 2 hours after lights on (2HALO) or 14 hours after lights on (14HALO). The severity of hypercalcemia and hyperphosphatemia was significantly milder when the drug was given at 14HALO. Serum concentrations of total OCT and albumin of the 2HALO and 14HALO trials did not differ significantly. The decrease of parathyroid hormone concentration was greater in the 14HALO trial while the increase in urinary ratio of Ca to creatinine was greater in the 2HALO trial. The suppression of urinary deoxypyridinoline excretion, an index of bone resorption capacity of osteoclast, and the increase in bone density of both femurs were greater in the 14HALO trial. These results suggest that the adverse reactions of OCT were ameliorated and its efficacy was enhanced after dosing of the drug at 14HALO. Chronopharmacological differences of OCT were more prominent than those seen with other vitamin D analogues. Dosing-time-dependent variation in the sensitivity of the drug to osteoclast were involved in the mechanisms of these events.
authors.affiliation: Department of Pharmacology, Division of Clinical Pharmacology, Jichi Medical School, 3311 Yakushiji Minamikawachi, Kawachi, Tochigi 329-0498, Japan. tsuru@jichi.ac.jp
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsuruoka
authors.forename: Kenta
authors.initials: K
authors.lastname: Nishiki
authors.forename: Michi
authors.initials: M
authors.lastname: Wakaumi
authors.forename: Hisahi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ando
authors.forename: Wang
authors.initials: W
authors.lastname: Ning
authors.forename: Akio
authors.initials: A
authors.lastname: Fujimura
mesh_terms: D000596:Amino Acids / Q000652:urine; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology*; D002118:Calcium / Q000097:blood / Q000652:urine; D019454:Chronotherapy / Q000379:methods*; D003404:Creatinine / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005269:Femur / Q000187:drug effects / Q000378:metabolism; D006934:Hypercalcemia / Q000097:blood / Q000139:chemically induced; D008297:Male; D009392:Nephrectomy; D010281:Parathyroid Hormone / Q000097:blood; D010710:Phosphates / Q000097:blood; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000596:Amino Acids; D010281:Parathyroid Hormone; D010710:Phosphates; C036020:deoxypyridinoline; D003404:Creatinine; D002117:Calcitriol; C051883:maxacalcitol; D002118:Calcium