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Investigations into the mechanisms of pyridine ring cleavage in vismodegibs

Khojasteh, SC and Yue, Q and Ma, S and Castanedo, G and Chen, JZ and Lyssikatos, J and Mulder, T and Takahashi, R and Ly, J and Messick, K and Jia, W and Liu, L and Hop, CECA and Wong, H (2014) Investigations into the mechanisms of pyridine ring cleavage in vismodegibs. Drug Metabolism and Disposition. pp. 343-351.

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 (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. Copyright 2014 by The American Society for Pharmacology and Experimental Therapeutics

Item Type: Article
Additional Information: NIBR author: Yue, Q institute: NIBR- address only contributor address: (Khojasteh, Yue, Ma, Chen, Mulder, Takahashi, Ly, Hop, Wong) Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States (Castanedo, Lyssikatos) Department of Discovery Chemistry, South San Francisco, CA, United States (Messick) GRED Non Clinical Operations, South San Francisco, California, United States (Jia) Small Molecule Pharmaceutical Sciences, South San Francisco, California, United States (Liu) Small Molecule Clinical Pharmacology, Genentech Inc., South San Francisco, CA, United States (Yue) Novartis Institutes for BioMedical Research, 4560 Horton St, Emeryville, CA 94608, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22650

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