RT Journal Article
SR Electronic
T1 Investigations into the Mechanisms of Pyridine Ring Cleavage in Vismodegib
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 343
OP 351
DO 10.1124/dmd.113.055715
VO 42
IS 3
A1 S. Cyrus Khojasteh
A1 Qin Yue
A1 Shuguang Ma
A1 Georgette Castanedo
A1 Jacob Z Chen
A1 Joseph Lyssikatos
A1 Teresa Mulder
A1 Ryan Takahashi
A1 Justin Ly
A1 Kirsten Messick
A1 Wei Jia
A1 Lichuan Liu
A1 Cornelis E. C. A. Hop
A1 Harvey Wong
YR 2014
UL http://dmd.aspetjournals.org/content/42/3/343.abstract
AB 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.