METABOLISM OF 26,26,26,27,27,27-F6-1α,23S,25-TRIHYDROXYVITAMIN D3 BY HUMAN UDP-GLUCURONOSYLTRANSFERASE 1A3*

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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.

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