title: Effects of i.v. and oral 1,25-dihydroxy-22-oxavitamin D(3) on secondary hyperparathyroidism in dogs with chronic renal failure.
abstract: BACKGROUND
  1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3), calcitriol) has been used for the treatment of secondary hyperparathyroidism (2HPT) associated with chronic renal failure (CRF). However, hypercalcaemia frequently precludes the administration of ideal doses of 1,25(OH)(2)D(3). 1,25-Dihydroxy-22-oxavitamin D(3) (22-oxacalcitriol, OCT) is an analogue of 1,25(OH)(2)D(3) with less calcaemic activity. Several investigators have reported the effect of this analogue on suppressing parathyroid hormone (PTH) in vitro and in vivo in rats and dogs.
  
  
  RESULTS
  The first experiments were designed to compare the relative potency of an i.v. injection of OCT and 1,25(OH)(2)D(3) (i.v. OCT vs i.v. 1,25(OH)(2)D(3)) on serum PTH and ionized calcium (ICa). A single dose of OCT (5 microg/kg) to uraemic dogs suppressed PTH by 81% without a statistical significant change in serum ICa. On the other hand, any of the effective doses of 1,25(OH)(2)D(3) on PTH suppression were hypercalcaemic. The intermittent administration of OCT (0.1 microg/kg) or 1,25(OH)(2)D(3) (0.025 microg/kg), three times per week i.v. suppressed serum PTH by 89 or 77%, respectively without hypercalcaemia. To evaluate OCT as an oral drug, it was given intermittently (three times per week) to a group of six dogs for a period of 4 weeks. Subsequently, it was changed to a daily administration (0.05 microg/kg) for a period of 2 weeks. Finally the dose was reduced to 0.025 microg/kg. Daily OCT 0.05 microg/kg suppressed serum PTH by 67%. Subsequently, 0.025 microg/kg maintained serum PTH within the normal range without hypercalcaemia for 4 weeks. The time course of serum OCT concentrations following a single i.v. or oral OCT dose to uraemic dogs showed that oral OCT was rapidly absorbed and reached maximum plasma concentration and its disappearance from blood was similar to that of i.v. injection.
  
  
  CONCLUSIONS
  In conclusion, our results suggest that OCT is a useful vitamin D(3) analogue, with a potentially larger therapeutic window than that of i.v. 1,25(OH)(2)D(3) and which is available for i.v./oral, in the management of 2HPT.
authors.affiliation: Chugai Pharmaceutical Co Ltd, Gotemba, Shizuoka, Japan. takahashifma@chugai-pharm.co.jp
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Takahashi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Furuichi
authors.forename: Keigo
authors.initials: K
authors.lastname: Yorozu
authors.forename: Setsu
authors.initials: S
authors.lastname: Kawata
authors.forename: Hidetomo
authors.initials: H
authors.lastname: Kitamura
authors.forename: Noboru
authors.initials: N
authors.lastname: Kubodera
authors.forename: Eduardo
authors.initials: E
authors.lastname: Slatopolsky
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002117:Calcitriol / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000627:therapeutic use*; D002118:Calcium / Q000097:blood; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy* / Q000209:etiology; D007275:Injections, Intravenous; D007676:Kidney Failure, Chronic / Q000150:complications*; D010281:Parathyroid Hormone / Q000097:blood; D012016:Reference Values; D014511:Uremia / Q000097:blood / Q000188:drug therapy
chemical_list: D010281:Parathyroid Hormone; D002117:Calcitriol; C051883:maxacalcitol; D002118:Calcium