Pharmacokinetics and systemic effect on calcium homeostasis of 1α,24-dihydroxyvitamin D 2 in rats comparison with 1α,25-Dihydroxyvitamin d 2, calcitriol, and calcipotriol

Abstract

1α,24-Dihydroxyvitamin D 2 (1α,24(OH) 2D 2) is a metabolite of 1α-hydroxyvitamin D 2 (1α-OH-D 2), a prodrug in development as a treatment for secondary hyperparathyroidism occurring in end stage renal disease. This prodrug has a broader therapeutic index than the corresponding vitamin D 3 analogue, possibly because hepatic metabolism of 1α-OH-D 2 shifts at higher dose levels from 1α,25-dihydroxyvitamin D 2 (1α,25(OH) 2D 2) to 1α,24(OH) 2D 2. In this report, we present the pharmacokinetics of 1α,24(OH) 2D 2 and its systemic effects on serum and urine calcium in rats. These properties were compared with those of 1α,25(OH) 2D 2, calcitriol, the active metabolite of endogenous vitamin D 3, and calcipotriol, a vitamin D analogue noted for its rapid clearance and minimal effect on calcium homeostasis. Comparison of the blood concentration curves from time zero to infinity indicated that 1α,24(OH) 2D 2 had about one-fifth the systemic exposure of 1α,25(OH) 2D 2 or calcitriol, but almost 30 times that of calcipotriol. The oral bioavailabilities and circulating half-lives of 1α,24(OH) 2D 2 and calcitriol were similar, whereas those of calcipotriol were much less. In vitamin D-deficient rats, oral doses of 1α,25(OH) 2D 2 and calcitriol produced similar dose-dependent increases in serum calcium, whereas an oral dose 30 times greater was required for lα,24(OH) 2D 2 to produce a similar response. Dose-response curves generated after oral and subcutaneous administration of 1α,24(OH) 2D 2, calcitriol, and calcipotriol to normal rats indicated that 1α,24(OH) 2D 2 increases serum and urine calcium to a much lesser extent than calcitriol, and to a slightly greater extent than calcipotriol. These properties of 1α,24(OH) 2D 2 suggest that production of this metabolite from 1α-OH-D 2 contributes to the lowered toxicity of 1α-OH-D 2 and indicate that 1α,24(OH) 2D 2 itself has therapeutic potential.