TY - JOUR T1 - Investigations into the Mechanisms of Pyridine Ring Cleavage in Vismodegib JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 343 LP - 351 DO - 10.1124/dmd.113.055715 VL - 42 IS - 3 AU - S. Cyrus Khojasteh AU - Qin Yue AU - Shuguang Ma AU - Georgette Castanedo AU - Jacob Z Chen AU - Joseph Lyssikatos AU - Teresa Mulder AU - Ryan Takahashi AU - Justin Ly AU - Kirsten Messick AU - Wei Jia AU - Lichuan Liu AU - Cornelis E. C. A. Hop AU - Harvey Wong Y1 - 2014/03/01 UR - http://dmd.aspetjournals.org/content/42/3/343.abstract N2 - Vismodegib (Erivedge, GDC-0449) is a first-in-class, orally administered small-molecule Hedgehog pathway inhibitor that is approved for the treatment of advanced basal cell carcinoma. Previously, we reported results from preclinical and clinical radiolabeled mass balance studies in which we determined that metabolism is the main route of vismodegib elimination. The metabolites of vismodegib are primarily the result of oxidation followed by glucuronidation. The focus of the current work is to probe the mechanisms of formation of three pyridine ring-cleaved metabolites of vismodegib, mainly M9, M13, and M18, using in vitro, ex vivo liver perfusion and in vivo rat studies. The use of stable-labeled (13C2,15N)vismodegib on the pyridine ring exhibited that the loss of carbon observed in both M9 and M13 was from the C-6 position of pyridine. Interestingly, the source of the nitrogen atom in the amide of M9 was from the pyridine. Evidence for the formation of aldehyde intermediates was observed using trapping agents as well as 18O-water. Finally, we conclude that cytochrome P450 is involved in the formation of M9, M13, and M18 and that M3 (the major mono-oxidative metabolite) is not the precursor for the formation of these cleaved products; rather, M18 is the primary cleaved metabolite. ER -