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The active vitamin D compound 1α,24(S)-dihydroxyvitamin D2 (1,24(OH)2D2) is under development as a therapy for disorders including cancer and secondary hyperparathyroidism. 1,24(OH)2D2 is a potent inhibitor of cell proliferation in vitro and, relative to calcitriol (1,25(OH)2D3), 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)2D2 or 1,25(OH)2D3 over 24 h. Serum levels of 1,24(OH)2D2 were lower than those of 1,25(OH)2D3 at all time points; however, tissue levels of radiolabeled compounds followed different patterns. In duodenum and kidney, 1,24(OH)2D2 and 1,25(OH)2D3 rose to similar levels at early time points; 1,24(OH)2D2 levels then declined more rapidly. In bone marrow, 1,24(OH)2D2 and 1,25(OH)2D3 were present at similar levels at all time points. In liver, 1,24(OH)2D2 levels were two-fold higher than 1,25(OH)2D3 at 1 h post-injection, declining to similar levels by 8 h. In vitamin D-deficient rats, doses of 1,24(OH)2D2 30-fold higher than 1,25(OH)2D3 were required to produce equal stimulation of intestinal calcium absorption. In the same deficient animals, 1,24(OH)2D2 and 1,25(OH)2D3 were nearly equipotent at stimulating bone calcium mobilization. In cultured bone cells, 1,24(OH)2D2 and 1,25(OH)2D3 were equipotent at stimulating osteoclast formation and bone resorption. In summary, the reduced calcemic activity of 1,24(OH)2D2 may result from altered pharmacokinetics relative to 1,25(OH)2D3, resulting in relatively rapid decreases in 1,24(OH)2D2 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)2D2.