Pharmacokinetics and systemic effect on calcium homeostasis of 1 alpha,24-dihydroxyvitamin D2 in rats. Comparison with 1 alpha,25-dihydroxyvitamin D2, calcitriol, and calcipotriol.

1 alpha,24-Dihydroxyvitamin D2 (1 alpha,24(OH)2D2) is a metabolite of 1 alpha-hydroxyvitamin D2 (1 alpha-OH-D2), 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 D3 analogue, possibly because hepatic metabolism of 1 alpha-OH-D2 shifts at higher dose levels from 1 alpha,25-dihydroxyvitamin D2 (1 alpha,25(OH)2D2) to 1 alpha,24(OH)2D2. In this report, we present the pharmacokinetics of 1 alpha,24(OH)2D2 and its systemic effects on serum and urine calcium in rats. These properties were compared with those of 1 alpha,25(OH)2D2, calcitriol, the active metabolite of endogenous vitamin D3, 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 1 alpha,24(OH)2D2 had about one-fifth the systemic exposure of 1 alpha,25(OH)2D2 or calcitriol, but almost 30 times that of calcipotriol. The oral bioavailabilities and circulating half-lives of 1 alpha,24(OH)2D2 and calcitriol were similar, whereas those of calcipotriol were much less. In vitamin D-deficient rats, oral doses of 1 alpha,25(OH)2D2 and calcitriol produced similar dose-dependent increases in serum calcium, whereas an oral dose 30 times greater was required for 1 alpha,24(OH)2D2 to produce a similar response. Dose-response curves generated after oral and subcutaneous administration of 1 alpha,24(OH)2D2, calcitriol, and calcipotriol to normal rats indicated that 1 alpha,24(OH)2D2 increases serum and urine calcium to a much lesser extent than calcitriol, and to a slightly greater extent than calcipotriol. These properties of 1 alpha,24(OH)2D2 suggest that production of this metabolite from 1 alpha-OH-D2 contributes to the lowered toxicity of 1 alpha-OH-D2 and indicate that 1 alpha,24(OH)2D2 contributes to the lowered toxicity of 1 alpha-OH-D2 and indicate that 1 alpha,24(OH)2D2 itself has therapeutic potential.