Abstract

26,26,26,27,27,27-Hexafluoro-1α,25(OH)₂ vitamin D₃, a hexafluorinated analog of 1α,25(OH)₂ vitamin D₃, has been reported to be several times more potent than the parent compound with respect to some vitamin D actions. The reason for enhanced biological activity in the bones, kidneys, and small intestine appears to be related to F₆-1α,25(OH)₂ vitamin D₃ metabolism to ST-232 (26,26,26,27,27,27-hexafluoro-1α,23S,25-trihydroxyvitamin D₃), a bioactive 23S-hydroxylated form that is resistant to further metabolism. We compared the disposition and metabolism of [1β-³H]F₆-1α,25(OH)₂ vitamin D₃ and [1β-³H]1α,25(OH)₂ vitamin D₃ in parathyroid glands of rats intravenously administered with labeled compounds at a dose of 10 μg/kg. In the [1β-³H]F₆-1α,25(OH)₂ vitamin D₃-dosed group, radioactivity was highly detected in the kidneys, parathyroid glands, and the small intestine. The radioactivity in the parathyroid glands remained high until 48 h postdosing, with values of 2.5, 8.4, and 14.6 times higher at 6, 24, and 48 h postdosing than after dosing with [1β-³H] 1α,25(OH)₂ vitamin D₃. In the group given [1β-³H]F₆-1α,25(OH)₂ vitamin D₃, the unchanged compound was mainly detected with a small amount of ST-232 at 6 h postdosing. At the 24- and 48-h time points, over half of the radioactivity was observed as ST-232, and additionally, ST-233, the 23-oxo form, accounted for a small amount at the 48-h time point. The present study demonstrated local retention of [1β-³H]F₆-1α,25(OH)₂ vitamin D₃ and the bioactive metabolite ST-232 in parathyroid glands after intravenous administration. The findings may indicate one of the reasons for the higher potency of F₆-1α,25(OH)₂ vitamin D₃ than 1α,25(OH)₂ vitamin D₃ in parathyroid.