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Research ArticleArticle

Structural and Kinetic Characterization of a Novel N-acetylated Aliphatic Amine Metabolite of the PRMT Inhibitor, EPZ011652

Nathalie Rioux, Lorna H. Mitchell, Philip Tiller, Katie Plant, Joanne Shaw, Kerry Frost, Scott Ribich, Mikel P. Moyer, Robert A. Copeland, Richard Chesworth and Nigel J. Waters
Drug Metabolism and Disposition July 2015, 43 (7) 936-943; DOI: https://doi.org/10.1124/dmd.115.064014
Nathalie Rioux
Epizyme, Cambridge, Massachusetts (N.R., L.H.M., S.R., M.P.M., R.A.C., R.C., N.J.W.); RMI Laboratories, North Wales, Pennsylvania (P.T.); and Cyprotex, Macclesfield, Cheshire, United Kingdom (K.P., J.S., K.F.)
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Lorna H. Mitchell
Epizyme, Cambridge, Massachusetts (N.R., L.H.M., S.R., M.P.M., R.A.C., R.C., N.J.W.); RMI Laboratories, North Wales, Pennsylvania (P.T.); and Cyprotex, Macclesfield, Cheshire, United Kingdom (K.P., J.S., K.F.)
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Philip Tiller
Epizyme, Cambridge, Massachusetts (N.R., L.H.M., S.R., M.P.M., R.A.C., R.C., N.J.W.); RMI Laboratories, North Wales, Pennsylvania (P.T.); and Cyprotex, Macclesfield, Cheshire, United Kingdom (K.P., J.S., K.F.)
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Katie Plant
Epizyme, Cambridge, Massachusetts (N.R., L.H.M., S.R., M.P.M., R.A.C., R.C., N.J.W.); RMI Laboratories, North Wales, Pennsylvania (P.T.); and Cyprotex, Macclesfield, Cheshire, United Kingdom (K.P., J.S., K.F.)
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Joanne Shaw
Epizyme, Cambridge, Massachusetts (N.R., L.H.M., S.R., M.P.M., R.A.C., R.C., N.J.W.); RMI Laboratories, North Wales, Pennsylvania (P.T.); and Cyprotex, Macclesfield, Cheshire, United Kingdom (K.P., J.S., K.F.)
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Kerry Frost
Epizyme, Cambridge, Massachusetts (N.R., L.H.M., S.R., M.P.M., R.A.C., R.C., N.J.W.); RMI Laboratories, North Wales, Pennsylvania (P.T.); and Cyprotex, Macclesfield, Cheshire, United Kingdom (K.P., J.S., K.F.)
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Scott Ribich
Epizyme, Cambridge, Massachusetts (N.R., L.H.M., S.R., M.P.M., R.A.C., R.C., N.J.W.); RMI Laboratories, North Wales, Pennsylvania (P.T.); and Cyprotex, Macclesfield, Cheshire, United Kingdom (K.P., J.S., K.F.)
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Mikel P. Moyer
Epizyme, Cambridge, Massachusetts (N.R., L.H.M., S.R., M.P.M., R.A.C., R.C., N.J.W.); RMI Laboratories, North Wales, Pennsylvania (P.T.); and Cyprotex, Macclesfield, Cheshire, United Kingdom (K.P., J.S., K.F.)
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Robert A. Copeland
Epizyme, Cambridge, Massachusetts (N.R., L.H.M., S.R., M.P.M., R.A.C., R.C., N.J.W.); RMI Laboratories, North Wales, Pennsylvania (P.T.); and Cyprotex, Macclesfield, Cheshire, United Kingdom (K.P., J.S., K.F.)
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Richard Chesworth
Epizyme, Cambridge, Massachusetts (N.R., L.H.M., S.R., M.P.M., R.A.C., R.C., N.J.W.); RMI Laboratories, North Wales, Pennsylvania (P.T.); and Cyprotex, Macclesfield, Cheshire, United Kingdom (K.P., J.S., K.F.)
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Nigel J. Waters
Epizyme, Cambridge, Massachusetts (N.R., L.H.M., S.R., M.P.M., R.A.C., R.C., N.J.W.); RMI Laboratories, North Wales, Pennsylvania (P.T.); and Cyprotex, Macclesfield, Cheshire, United Kingdom (K.P., J.S., K.F.)
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Abstract

Pharmacokinetic and metabolite identification studies were conducted to understand the clearance pathways of EPZ011652 [(2-aminoethyl)(methyl)({3-[4-(propan-2-yloxy)phenyl]-1H-pyrazol-4-yl}methyl)amine], a potent protein arginine N-methyltransferase inhibitor. Metabolic clearance was the major pathway of EPZ011652 elimination in rats with structural elucidation of metabolites via liquid chromatography - mass spectrometry (LC-MSn) accurate mass measurement revealing the formation of a novel aliphatic N-acetylated metabolite (M1) located on the terminal nitrogen of the ethylene-diamine side chain. EPZ015564, a synthetic standard of the N-acetyl product, was prepared and was also generated by human and rat, but not dog hepatocytes. In rat hepatocytes, on incubation with EPZ011652, the concentration of EPZ015564 initially increased before decreasing with incubation time, suggesting that the metabolite is itself a substrate for other metabolizing enzymes, in agreement with the identification of metabolites M2, M3, and M4 in rat bile, all N-acetylated metabolites, undergoing sequential phase I (demethylation, oxidation) or phase II (sulfation) reactions. Reaction phenotyping with recombinant human N-acetyltransferase (NAT) isoforms revealed that both NAT1 and NAT2 are capable of acetylating EPZ011652, although with different catalytic efficiencies. Kinetic profiles of EPZ015564 formation followed classic Michaelis-Menten behavior with apparent Km values of >1000 μM for NAT1 and 165 ± 14.1 µM for NAT2. The in vitro intrinsic clearance for EPZ011652 by NAT2 (110 μL/min/mg) was 500-fold greater than by NAT1. In summary, we report the unusual N-acetylation of an aliphatic amine and discuss the implications for drug discovery and clinical development.

Footnotes

    • Received February 26, 2015.
    • Accepted April 17, 2015.
  • dx.doi.org/10.1124/dmd.115.064014.

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

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (7)
Drug Metabolism and Disposition
Vol. 43, Issue 7
1 Jul 2015
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Research ArticleArticle

Characterization of a Novel N-Acetylation Pathway

Nathalie Rioux, Lorna H. Mitchell, Philip Tiller, Katie Plant, Joanne Shaw, Kerry Frost, Scott Ribich, Mikel P. Moyer, Robert A. Copeland, Richard Chesworth and Nigel J. Waters
Drug Metabolism and Disposition July 1, 2015, 43 (7) 936-943; DOI: https://doi.org/10.1124/dmd.115.064014

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Research ArticleArticle

Characterization of a Novel N-Acetylation Pathway

Nathalie Rioux, Lorna H. Mitchell, Philip Tiller, Katie Plant, Joanne Shaw, Kerry Frost, Scott Ribich, Mikel P. Moyer, Robert A. Copeland, Richard Chesworth and Nigel J. Waters
Drug Metabolism and Disposition July 1, 2015, 43 (7) 936-943; DOI: https://doi.org/10.1124/dmd.115.064014
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