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Research ArticleArticle

Novel Mechanism of Decyanation of GDC-0425 by Cytochrome P450

Ryan H. Takahashi, Jason S. Halladay, Michael Siu, Yuan Chen, Cornelis E. C. A. Hop, S. Cyrus Khojasteh and Shuguang Ma
Drug Metabolism and Disposition May 2017, 45 (5) 430-440; DOI: https://doi.org/10.1124/dmd.116.074336
Ryan H. Takahashi
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California
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Jason S. Halladay
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California
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Michael Siu
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California
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Yuan Chen
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California
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Cornelis E. C. A. Hop
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California
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S. Cyrus Khojasteh
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California
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Shuguang Ma
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., J.S.H., Y.C., C.E.C.A.H., S.C.K., S.M.), and Discovery Chemistry (M.S.), Genentech, Inc., 1 DNA Way, South San Francisco, California
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Abstract

GDC-0425 [5-((1-ethylpiperidin-4-yl)oxy)-9H-pyrrolo[2,3-b:5,4-c']dipyridine-6-carbonitrile] is an orally bioavailable small-molecule inhibitor of checkpoint kinase 1 that was investigated as a novel cotherapy to potentiate chemotherapeutic drugs, such as gemcitabine. In a radiolabeled absorption, distribution, metabolism, and excretion study in Sprague-Dawley rats, trace-level but long-lived 14C-labeled thiocyanate was observed in circulation. This thiocyanate originated from metabolic decyanation of GDC-0425 and rapid conversion of cyanide to thiocyanate. Excretion studies indicated decyanation was a minor metabolic pathway, but placing 14C at nitrile magnified its observation. Cytochrome P450s catalyzed the oxidative decyanation reaction in vitro when tested with liver microsomes, and in the presence of 18O2, one atom of 18O was incorporated into the decyanated product. To translate this finding to a clinical risk assessment, the total circulating levels of thiocyanate (endogenous plus drug-derived) were measured following repeated administration of GDC-0425 to rats and cynomolgus monkeys. No overt increases were observed with thiocyanate concentrations of 121–154 µM in rats and 71–110 µM in monkeys receiving vehicle and all tested doses of GDC-0425. These findings were consistent with results from the radiolabel rat study where decyanation accounted for conversion of <1% of the administered GDC-0425 and contributed less than 1 µM thiocyanate to systemic levels. Further, in vitro studies showed only trace oxidative decyanation for humans. These data indicated that, although cyanide was metabolically released from GDC-0425 and formed low levels of thiocyanate, this pathway was a minor route of metabolism, and GDC-0425–related increases in systemic thiocyanate were unlikely to pose safety concerns for subjects of clinical studies.

Footnotes

    • Received November 17, 2016.
    • Accepted February 7, 2017.
  • ↵1 Current affiliation: Department of Drug Metabolism and Pharmacokinetics, Anacor Pharmaceuticals, Inc., Palo Alto, California.

  • https://doi.org/10.1124/dmd.116.074336.

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

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 45 (5)
Drug Metabolism and Disposition
Vol. 45, Issue 5
1 May 2017
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Research ArticleArticle

Trace Circulating Thiocyanate Is Derived from GDC-0425

Ryan H. Takahashi, Jason S. Halladay, Michael Siu, Yuan Chen, Cornelis E. C. A. Hop, S. Cyrus Khojasteh and Shuguang Ma
Drug Metabolism and Disposition May 1, 2017, 45 (5) 430-440; DOI: https://doi.org/10.1124/dmd.116.074336

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Research ArticleArticle

Trace Circulating Thiocyanate Is Derived from GDC-0425

Ryan H. Takahashi, Jason S. Halladay, Michael Siu, Yuan Chen, Cornelis E. C. A. Hop, S. Cyrus Khojasteh and Shuguang Ma
Drug Metabolism and Disposition May 1, 2017, 45 (5) 430-440; DOI: https://doi.org/10.1124/dmd.116.074336
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