PHARMACOKINETICS AND SYSTEMIC EFFECT ON CALCIUM HOMEOSTASIS OF 1-ALPHA,24-DIHYDROXYVITAMIN D-2 IN RATS - COMPARISON WITH 1-ALPHA,25-DIHYDROXYVITAMIN D-2, CALCITRIOL, AND CALCIPOTRIOL

1 alpha,24-Dihydroxyvitamin D-2 (1 alpha,24(OH)(2)D-2) is a metabolite of 1 alpha-hydroxyvitamin D-2 (1 alpha-OH-D-2), a prodrug in developm ent 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 meta bolism of 1 alpha-OH-D-2 shifts at higher dose levels from 1 alpha,25- dihydroxyvitamin D-2 (1 alpha,25(OH)(2)D-2) to 1 alpha,24(OH)(2)D-2. I n this report, we present the pharmacokinetics of 1 alpha,24(OH)(2)D-2 and its systemic effects on serum and urine calcium in rats. These pr operties were compared with those of 1 alpha,25(OH)(2)D-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 fro m time zero to infinity indicated that 1 alpha,24(OH)(2)D-2 had about one-fifth the systemic exposure of 1 alpha,25(OH)(2)D-2 or calcitriol, but almost 30 times that of calcipotriol. The oral bioavailabilities and circulating half-lives of 1 alpha,24(OH)(2)D-2 and calcitriol were similar, whereas those of calcipotriol were much less. In vitamin D-d eficient rats, oral doses of 1 alpha,25(OH)(2)D-2 and calcitriol produ ced similar dose-dependent increases in serum calcium, whereas an oral dose 30 times greater was required for 1 alpha,24(OH)(2)D-2 to produc e a similar response. Dose-response curves generated after oral and su bcutaneous administration of 1 alpha,24(OH)(2)D-2, calcitriol, and cal cipotriol to normal rats indicated that 1 alpha,24(OH)(2)D-2 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)(2)D-2 suggest that production of this metabolite from 1 a lpha-OH-D-2 contributes to the lowered toxicity of 1 alpha-OH-D-2 and indicate that 1 alpha,24(OH)(2)D-2 itself has therapeutic potential. ( C) 1997 Elsevier Science Inc.