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Research ArticleArticle

Investigations into the Mechanisms of Pyridine Ring Cleavage in Vismodegib

S. Cyrus Khojasteh, Qin Yue, Shuguang Ma, Georgette Castanedo, Jacob Z Chen, Joseph Lyssikatos, Teresa Mulder, Ryan Takahashi, Justin Ly, Kirsten Messick, Wei Jia, Lichuan Liu, Cornelis E. C. A. Hop and Harvey Wong
Drug Metabolism and Disposition March 2014, 42 (3) 343-351; DOI: https://doi.org/10.1124/dmd.113.055715
S. Cyrus Khojasteh
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
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Qin Yue
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
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Shuguang Ma
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
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Georgette Castanedo
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
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Jacob Z Chen
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
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Joseph Lyssikatos
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
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Teresa Mulder
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
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Ryan Takahashi
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
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Justin Ly
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
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Kirsten Messick
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
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Wei Jia
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
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Lichuan Liu
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
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Cornelis E. C. A. Hop
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
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Harvey Wong
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
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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.

Footnotes

    • Received November 6, 2013.
    • Accepted December 11, 2013.
  • ↵1 Current affiliation: Novartis Institutes for BioMedical Research, 4560 Horton St, Emeryville, CA 94608

  • S.C.K., Q.Y., and S.M. contributed equally to this work.

  • dx.doi.org/10.1124/dmd.113.055715.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (3)
Drug Metabolism and Disposition
Vol. 42, Issue 3
1 Mar 2014
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Research ArticleArticle

Pyridine Ring Cleavage of Vismodegib

S. Cyrus Khojasteh, Qin Yue, Shuguang Ma, Georgette Castanedo, Jacob Z Chen, Joseph Lyssikatos, Teresa Mulder, Ryan Takahashi, Justin Ly, Kirsten Messick, Wei Jia, Lichuan Liu, Cornelis E. C. A. Hop and Harvey Wong
Drug Metabolism and Disposition March 1, 2014, 42 (3) 343-351; DOI: https://doi.org/10.1124/dmd.113.055715

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Research ArticleArticle

Pyridine Ring Cleavage of Vismodegib

S. Cyrus Khojasteh, Qin Yue, Shuguang Ma, Georgette Castanedo, Jacob Z Chen, Joseph Lyssikatos, Teresa Mulder, Ryan Takahashi, Justin Ly, Kirsten Messick, Wei Jia, Lichuan Liu, Cornelis E. C. A. Hop and Harvey Wong
Drug Metabolism and Disposition March 1, 2014, 42 (3) 343-351; DOI: https://doi.org/10.1124/dmd.113.055715
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