title: Investigations into the mechanisms of pyridine ring cleavage in vismodegib.
abstract: 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 ((13)C2,(15)N)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 (18)O-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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics (S.C.K., Q.Y., S.M., J.Z.C., T.M., R.T., J.L., C.E.C.A., H.W.), Department of Discovery Chemistry (G.C., J.L.), gRED Non Clinical Operations (K.M.), Small Molecule Pharmaceutical Sciences (W.J.), and Small Molecule Clinical Pharmacology (L.L.), Genentech Inc., South San Francisco, California.
authors.forename: S Cyrus
authors.initials: SC
authors.lastname: Khojasteh
authors.forename: Qin
authors.initials: Q
authors.lastname: Yue
authors.forename: Shuguang
authors.initials: S
authors.lastname: Ma
authors.forename: Georgette
authors.initials: G
authors.lastname: Castanedo
authors.forename: Jacob Z
authors.initials: JZ
authors.lastname: Chen
authors.forename: Joseph
authors.initials: J
authors.lastname: Lyssikatos
authors.forename: Teresa
authors.initials: T
authors.lastname: Mulder
authors.forename: Ryan
authors.initials: R
authors.lastname: Takahashi
authors.forename: Justin
authors.initials: J
authors.lastname: Ly
authors.forename: Kirsten
authors.initials: K
authors.lastname: Messick
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.forename: Lichuan
authors.initials: L
authors.lastname: Liu
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
mesh_terms: D000813:Anilides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010477:Perfusion; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000813:Anilides; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; C023666:pyridine