title: 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.
abstract: 1. 26,26,26,27,27,27-F6,-1,25(OH)2 vitamin D3, Falecalcitriol, the hexafluorinated analogue of 1,25(OH)2 vitamin D3, 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 F6-1,25(OH)2 vitamin D3 metabolism to F6-1,23S,25(OH)3 vitamin D3, a bioactive 23S-hydroxylated form which is resistant to further metabolism. 2. In the present in vivo studies, the repeated oral administration of [3H]F6-1,25(OH)2 vitamin D3 to rat resulted in a significant reduction of the radioactivity and the F6-1,25(OH)2 vitamin D3 concentrations in serum, especially at the 2 h maximum point after each dosing. Additionally, F6-1,23S,25(OH)3 vitamin D3 in the serum and small intestine was increased by the prior administration of F6-1,25(OH)2 vitamin D3. 3. Further in vitro investigation showed [3H]F6-1,25(OH)2 vitamin D3 to be metabolized to F6-1,23S,25(OH)3 vitamin D3 by kidney and small intestine homogenates of rat, the reaction being increased by the prior administration of F6-1,25(OH)2 vitamin D3. 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 F6-1,25(OH)2 vitamin D3 to F6-1,23S,25(OH)3 vitamin D3 is catalysed by CYP24, the enzyme being induced by prior substrate exposure.
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd, Osaka, Japan. komuro@sc.sumitomo-chem.co.jp
authors.forename: S
authors.initials: S
authors.lastname: Komuro
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.forename: H
authors.initials: H
authors.lastname: Kanamaru
authors.forename: H
authors.initials: H
authors.lastname: Kaneko
authors.forename: I
authors.initials: I
authors.lastname: Nakatsuka
authors.forename: A
authors.initials: A
authors.lastname: Yoshitake
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015152:Blotting, Northern; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D006900:Hydroxylation / Q000187:drug effects; D007421:Intestine, Small / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013250:Steroid Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D014018:Tissue Distribution; D065668:Vitamin D3 24-Hydroxylase; D005466:Fluorocarbons
chemical_list: D002117:Calcitriol; D003577:Cytochrome P-450 Enzyme System; D012333:RNA, Messenger; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; C040488:26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3; D005466:Fluorocarbons