Metabolism of a cyclopropane-ring-containing analog of 1 alpha-hydroxyvitamin D3 in a hepatocyte cell model. Identification of 24-oxidized metabolites.

MC969 is an analog of the calcemic drug 1 alpha-hydroxyvitamin D3 (1 alpha-OH-D3) in which carbons 25,26, and 27 in the side chain are incorporated into a cyclopropane ring. Metabolites of MC 969 were generated in an in vitro human hepatocyte cell model, Hep 3B. The identity of the metabolites was established by comigration on HPLC with authentic standards, and by mass spectrometry of native and chemically modified metabolites. Unequivocal identification of the 24-keto- and the two epimeric 24-alcohol metabolites is provided. No 25-hydroxylated metabolites were detected. In competition studies, MC 969 was able to inhibit 25-hydroxylation of tritiated vitamin D3 more effectively than 1 alpha-OH-D3 itself, indicating that the vitamin D3-25-hydroxylase may be responsible for generation of one or more of the metabolites observed.