Effects of i.v. and oral 1,25-dihydroxy-22-oxavitamin D(3) on secondary hyperparathyroidism in dogs with chronic renal failure.
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.
Takahashi
Fumiaki
F
Chugai Pharmaceutical Co Ltd, Gotemba, Shizuoka, Japan. takahashifma@chugai-pharm.co.jp
Furuichi
Tatsuya
T
Yorozu
Keigo
K
Kawata
Setsu
S
Kitamura
Hidetomo
H
Kubodera
Noboru
N
Slatopolsky
Eduardo
E
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
D010281:Parathyroid Hormone; D002117:Calcitriol; C051883:maxacalcitol; D002118:Calcium