Tissue distribution and activity studies of 1,24-dihydroxyvitamin D2, a metabolite of vitamin D2 with low calcemic activity in vivo

Abstract The active vitamin D compound 1α,24( S )-dihydroxyvitamin D 2 (1,24(OH) 2 D 2 ) is under development as a therapy for disorders including cancer and secondary hyperparathyroidism. 1,24(OH) 2 D 2 is a potent inhibitor of cell proliferation in vitro and, relative to calcitriol (1,25(OH) 2 D 3 ), has reduced calcemic activity in vivo. To examine the mechanisms underlying this reduced calcemic activity, we studied the tissue distribution in rats of radiolabeled 1,24(OH) 2 D 2 or 1,25(OH) 2 D 3 over 24 h. Serum levels of 1,24(OH) 2 D 2 were lower than those of 1,25(OH) 2 D 3 at all time points; however, tissue levels of radiolabeled compounds followed different patterns. In duodenum and kidney, 1,24(OH) 2 D 2 and 1,25(OH) 2 D 3 rose to similar levels at early time points; 1,24(OH) 2 D 2 levels then declined more rapidly. In bone marrow, 1,24(OH) 2 D 2 and 1,25(OH) 2 D 3 were present at similar levels at all time points. In liver, 1,24(OH) 2 D 2 levels were two-fold higher than 1,25(OH) 2 D 3 at 1 h post-injection, declining to similar levels by 8 h. In vitamin D-deficient rats, doses of 1,24(OH) 2 D 2 30-fold higher than 1,25(OH) 2 D 3 were required to produce equal stimulation of intestinal calcium absorption. In the same deficient animals, 1,24(OH) 2 D 2 and 1,25(OH) 2 D 3 were nearly equipotent at stimulating bone calcium mobilization. In cultured bone cells, 1,24(OH) 2 D 2 and 1,25(OH) 2 D 3 were equipotent at stimulating osteoclast formation and bone resorption. In summary, the reduced calcemic activity of 1,24(OH) 2 D 2 may result from altered pharmacokinetics relative to 1,25(OH) 2 D 3 , resulting in relatively rapid decreases in 1,24(OH) 2 D 2 levels and activity in target organs such as intestine. Further studies will be necessary to confirm these findings and to confirm the clinical utility of 1,24(OH) 2 D 2 .