The Vitamin D Analog, KH1060, Is Rapidly Degraded Both in Vivo and in Vitro via Several Pathways: Principal Metabolites Generated Retain Significant Biological Activity

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Abstract
Vitamin D analogs are valuable drugs with established and po- tential uses in hyperproliferative disorders. Lexacalcitol (KH1060) is over 100 times more active than 1a,25-dihydroxyvitamin D3 (1a,25- (OH)2D3), as judged by in vitro antiproliferative and cell differenti- ating assays. The underlying biochemical reasons for the increased biological activity of KH1060 are unknown, but are thought to include 1) metabolic considerations in addition to explanations based upon 2) enhanced stability of KH1060-liganded transcriptional complexes. In this study we explored the in vivo and in vitro metabolism of KH1060. We established by physicochemical techniques the existence of mul- tiple side-chain hydroxylated metabolites of KH1060, including 24-, 24a-, 26-, and 26a-hydroxylated derivatives as well as side-chain truncated forms. KH1060 metabolism could be blocked by the cyto- chrome P450 inhibitor, ketoconazole. KH1060 was not an effective

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