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26,27-Hexafluoro-1 alpha,25-dihydroxyvitamin D3 [F6-1,25-(OH)2D3] is more potent than 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] in stimulating bone resorption in vitro and in vivo. The reason why F6-1,25(OH)2D3 is more active remains unclear. To clarify the relationship between the bone-resorbing activity of each vitamin D3 analogue and the metabolism of each analogue, in the present study, we used an ex vivo method that was established by Reynolds et al (Calcif Tissue Res, 1974, 15, 333-339). The effect of F6-1,25(OH)2D3 or 1,25(OH)2D3 on 45Ca release from parietal bones, prepared at 3, 14 and 24 h after injection of 1.9, 3.8, 7.6 or 15.2 pmol vitamin D analog/g body weight, was examined. F6-1,25(OH)2D3 was more potent than 1,25(OH)2D3 during each in vivo time period. 1,25(OH)2D3 at 3 h after the injection was more active compared to the control (no injection of 1,25(OH)2D3) but not at 14 and 24 h. The radioactivity of the bones after the injection of [3H]-F6-1,25(OH)2D3 was retained even at 24 h. In the case of [3H]-1,25(OH)2D3, the radioactivity of bones decreased with an increase in the in vivo period. In a HPLC analysis of the lipid extract of bone homogenate, [3H]-F6-1,25(OH)2D3 alone was detected at 3 h after the injection and both [3H]-F6-1,25(OH)2D3 and [3H]-26,27-hexafluoro-1 alpha, 23S,25-trihydroxyvitamin D3 [F6-1,23,25(OH)3D3] were detected at 14 and 24 h after the injection. [3H]-1,25(OH)2D3 was highly detected at 3 h after the injection, but it decreased with an increase in the in vivo period. In the ex vivo test, the activity of F6-1,23,25(OH)3D3 was less than that of F6-1,25(OH)2D3 but similar to that of 1,25(OH)2D3. The present study indicates that F6-1,25(OH)2D3 is more active and more long-lasting than 1,25(OH)2D3 in the ex vivo method. A higher potency of F6-1,25(OH)2D3 is explained, at least partly, by the results that the amounts of both F6-1,25(OH)2D3 and its active metabolite, F6-1,23,25(OH)3D3, in the bones are higher than that of 1,25(OH)2D3, and that F6-1,25(OH)2D3 and its metabolite are retained in bones longer than 1,25(OH)2D3.

Comparison of 26,27-Hexafluoro-1.ALPHA.,25-dihydroxyvitamin D3 and 1.ALPHA.,25-Dihydroxyvitamin D3 on the Resorption of Bone Explants Ex Vivo.