Abstract

26,26,26,27,27,27-Hexafluoro-1α,25-dihydroxyvitamin D₃ [F₆-1α, 25(OH)₂D₃], which is now clinically used as a drug for secondary hyperparathyroidism, is a hexafluorinated analog of the active form of vitamin D₃. Our previous studies demonstrated that CYP24A1 is responsible for the metabolism of F₆-1α,25(OH)₂D₃ in the target tissues and that F₆-1α,25(OH)₂D₃ was successively converted to F₆-1α,23S,25(OH)₃D₃ and F₆-23-oxo-1α,25(OH)₂D₃. In this study, we examined the metabolism of F₆-1α,25(OH)₂D₃,F₆-1α,23S,25(OH)₃D₃, and F₆-23-oxo-1α,25(OH)₂D₃ by human UDP-glucuronosyltransferases (UGTs). Of these compounds, F₆-1α,23S,25(OH)₃D₃ was remarkably glucuronidated both in human liver microsomes and in the recombinant system expressing human UGT. No significant interindividual differences were observed among 10 human liver samples. The recombinant system for 12 species of human UGTs revealed that F₆-1α,23S,25(OH)₃D₃ glucuronidation was specifically catalyzed by UGT1A3. The information obtained in this study seems very useful to predict the metabolism and efficacy of vitamin D analogs in human bodies before clinical trials. In addition, note that for the first time a possible probe substrate for UGT1A3 has been found.