Antagonistic actions in vivo of (23S)-25-dehydro-1 alpha-hydroxyvitamin D-3,26,23-lactone on calcium metabolism induced by 1 alpha,25-dihydroxyvitamin D-3

The vitamin D analog, (23S)-25-dehydro-1 alpha -hydroxyvitamin D-3-26,23-la ctone (TEI-9647), is an antagonist of the 1 alpha ,25-dihydroxyvitamin D-3 [1 alpha ,25(OH)(2)D-3] nuclear receptor (VDR)-mediated differentiation of human leukemia (HL-60) cells. To clarify whether TEI-9647 could function as an antagonist of 1 alpha ,25(OH)(2)D-3 in vivo, we investigated in vitamin D-deficient (-D) rats the effects of single doses of TEI-9647 on several p arameters of calcium metabolism modulated by 1 alpha ,25(OH)(2)D-3. TEI-964 7 (50 mug/kg iv) acting alone slightly, but significantly, stimulated intes tinal calcium transport (ICA) and bone calcium mobilization (BCM) only at 8 h, but not at 24 h. In contrast, TEI-9647 dose-dependently inhibited ICA a nd BCM stimulated by an iv dose of 0.25 mug/kg 1 alpha ,25(OH)(2)D-3 after 24 h, but not after 8 h. With respect to serum PTH levels, the administrati on of either TEI-9647, 50 mug/kg, or 1 alpha ,25(OH)(2)D-3, 0.25 mug/kg, be gan to decrease the circulating levels by 4 h, which reached a nadir 24 h a fter administration. But, when TEI-9647 and 1 alpha ,25(OH)(2)D-3 were simu ltaneously administered to -D rats, the TEI-9647 dose-dependently reversed the inhibition of PTH secretion caused by 1 alpha ,25(OH)(2)D-3, 0.25 mug/k g, at 8 and 24 h after the treatment. In separate experiments, the daily iv administration of 20 mug/kg of TEI 9647 alone to +D rats for 2 weeks resul ted in no significant changes in the prevailing serum Ca2+ concentration. B ut doses of 1-20 mug/kg of TEI-9647 in combination with 0.5 mug/kg of 1 alp ha ,25(OH)(2)D-3, for 2 weeks, dose-dependently and significantly suppresse d the serum calcium concentration increase caused by the 1 alpha ,25(OH)(2) D-3. Collectively, these results show that TEI-9647 acting alone displays i n vivo weak agonistic actions, but when administered in combination with 1 alpha ,25(OH)(2)D-3, is a potent antagonist of three genomic-mediated calci um metabolism parameters. We conclude that TEI-9647 can also function as an antagonist of 1 alpha ,25(OH)(2)D-3 in vivo in the rat.