Effects of i.v. and oral 1,25-dihydroxy-22-oxavitamin D3 on secondary hyperparathyroidism in dogs with chronic renal failure

Abstract

Background. 1,25-Dihydroxyvitamin D3(1,25(OH)2D3, 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)2D3. 1,25-Dihydroxy-22-oxavitamin D3 (22-oxacalcitriol, OCT) is an analogue of 1,25(OH)2D3 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. Methods and Results. The first experiments were designed to compare the relative potency of an i.v. injection of OCT and 1,25(OH)2D3 (i.v. OCT vs i.v. 1,25(OH)2D3) on serum PTH and ionized calcium (ICa). A single dose of OCT (5 μg/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)2D3 on PTH suppression were hypercalcaemic. The intermittent administration of OCT (0.1 μg/kg) or 1,25(OH)2D3 (0.025 μg/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 μg/kg) for a period of 2 weeks. Finally the dose was reduced to 0.025 μg/kg. Daily OCT 0.05 μg/kg suppressed serum PTH by 67%. Subsequently, 0.025 μg/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 D3 analogue, with a potentially larger therapeutic window than that of i.v. 1,25(OH)2D3 and which is available for i.v./oral, in the management of 2HPT.