In vivo and in vitro pharmacokinetics and metabolism studies of 26,26,26,27,27,27-F6-1,25(OH)2 vitamin D3 (Falecalcitriol) in rat:: induction of vitamin D3-24-hydroxylase (CYP24) responsible for 23S-hydroxylation in target tissues and the drop in serum levels

1. 26,26,26,27,27,27-F-6-1,25(OH)(2) vitamin D-3, Falecalcitriol, the hexafluorinated analogue of 1,25(OH)(2) vitamin D-3, has been reported to be several times more potent than the parent compound regarding some vitamin D actions. The reason for enhanced biological activity appears related to F-6-1,25(OH)(2) vitamin D-3 metabolism to F-6- 1,23S,25(OH)(3) vitamin D-3, a bioactive 23S-hydroxylated form which is resistant to further metabolism. 2. In the present in vivo studies, the repeated oral administration of [H-3]F-6-1,25(OH)(2) vitamin D-3 to rat resulted in a significant reduction of the radioactivity and the F-6-1,25(OH)(2) vitamin D-3 concentrations in serum, especially at the 2 h maximum point after each dosing. Additionally, F-6-1,23S,25(OH)(3) vitamin D-3 in the serum and small intestine was increased by the prior administration of F-6-1,25(OH)(2) vitamin D-3. 3. Further in vitro investigation showed [H-3]F-6-1,25(OH)(2) vitamin D to be metabolized to F-6-1,23S,25(OH)(3) vitamin D-3 by kidney and small intestine homogenates of rat, the reaction being increased by the prior administration of F-6-1,25(OH)(2) vitamin D-3. Moreover, this latter treatment was associated with a marked increase of CYP24 mRNA in the small intestine within 4 h after dosing. 4. The results indicate that in vivo metabolism of F-6-1,25(OH)(2) vitamin D-3 to F-6-1,23S,25(OH)(2) vitamin D-3 is catalysed by CYP24, the enzyme being induced by prior substrate exposure.