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Research ArticleArticle

Investigation into MAO B–Mediated Formation of CC112273, a Major Circulating Metabolite of Ozanimod, in Humans and Preclinical Species: Stereospecific Oxidative Deamination of (S)-Enantiomer of Indaneamine (RP101075) by MAO B

April Bai, Veerabahu Shanmugasundaram, Julie V. Selkirk, Sekhar Surapaneni and Deepak Dalvie
Drug Metabolism and Disposition August 2021, 49 (8) 601-609; DOI: https://doi.org/10.1124/dmd.121.000447
April Bai
Non-clinical Research and Development (A.B., D.D.) and Neuroscience TRC (J.V.S.), Bristol-Myers Squibb, San Diego, California; Molecular Structure and Design, Bristol-Myers Squibb, Cambridge, Massachusetts (V.S.); and Non-clinical Research and Development, Bristol-Myers Squibb, Summit, New Jersey (S.S.)
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Veerabahu Shanmugasundaram
Non-clinical Research and Development (A.B., D.D.) and Neuroscience TRC (J.V.S.), Bristol-Myers Squibb, San Diego, California; Molecular Structure and Design, Bristol-Myers Squibb, Cambridge, Massachusetts (V.S.); and Non-clinical Research and Development, Bristol-Myers Squibb, Summit, New Jersey (S.S.)
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Julie V. Selkirk
Non-clinical Research and Development (A.B., D.D.) and Neuroscience TRC (J.V.S.), Bristol-Myers Squibb, San Diego, California; Molecular Structure and Design, Bristol-Myers Squibb, Cambridge, Massachusetts (V.S.); and Non-clinical Research and Development, Bristol-Myers Squibb, Summit, New Jersey (S.S.)
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Sekhar Surapaneni
Non-clinical Research and Development (A.B., D.D.) and Neuroscience TRC (J.V.S.), Bristol-Myers Squibb, San Diego, California; Molecular Structure and Design, Bristol-Myers Squibb, Cambridge, Massachusetts (V.S.); and Non-clinical Research and Development, Bristol-Myers Squibb, Summit, New Jersey (S.S.)
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Deepak Dalvie
Non-clinical Research and Development (A.B., D.D.) and Neuroscience TRC (J.V.S.), Bristol-Myers Squibb, San Diego, California; Molecular Structure and Design, Bristol-Myers Squibb, Cambridge, Massachusetts (V.S.); and Non-clinical Research and Development, Bristol-Myers Squibb, Summit, New Jersey (S.S.)
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Abstract

Ozanimod, recently approved for treating relapsing multiple sclerosis, produced a disproportionate, active, MAO B–catalyzed metabolite (CC112273) that showed remarkable interspecies differences and led to challenges in safety testing. This study explored the kinetics of CC112273 formation from its precursor RP101075. Incubations with human liver mitochondrial fractions revealed KMapp, Vmax, and intrinsic clearance (Clint) for CC112273 formation to be 4.8 μM, 50.3 pmol/min/mg protein, and 12 μl/min/mg, respectively, whereas Michaelis-Menten constant (KM) with human recombinant MAO B was 1.1 μM. Studies with liver mitochondrial fractions from preclinical species led to KMapp, Vmax, and Clint estimates of 3.0, 35, and 33 μM, 80.6, 114, 37.3 pmol/min/mg, and 27.2, 3.25, and 1.14 μl/min/mg in monkey, rat, and mouse, respectively, and revealed marked differences between rodents and primates, primarily attributable to differences in the KM. Comparison of Clint estimates revealed monkey to be ∼2-fold more efficient and the mouse and rat to be 11- and 4-fold less efficient than humans in CC112273 formation. The influence of stereochemistry on MAO B–mediated oxidation was also investigated using the R-isomer of RP101075 (RP101074). This showed marked selectivity toward catalysis of the S-isomer (RP101075) only. Docking into MAO B crystal structure suggested that although both the isomers occupied its active site, only the orientation of RP101075 presented the C-H on the α-carbon that was ideal for the C-H bond cleavage, which is a requisite for oxidative deamination. These studies explain the basis for the observed interspecies differences in the metabolism of ozanimod as well as the substrate stereospecificity for formation of CC112273.

SIGNIFICANCE STATEMENT This study evaluates the enzymology and the species differences of the major circulating metabolite of ozanimod, CC112273. Additionally, the study also explores the influence of stereochemistry on MAO B–catalyzed reactions. The study is of significance to the DMD readers given that this oxidation is catalyzed by a non–cytochrome P450 enzyme, and that marked species difference and notable stereospecificity was observed in MAO B–catalyzed biotransformation when the indaneamine enantiomers were used as substrates.

Footnotes

    • Received March 8, 2021.
    • Accepted May 3, 2021.
  • This work did not receive external funding.

  • All the authors are employees of Bristol-Myers Squibb (BMS).

  • https://dx.doi.org/10.1124/dmd.121.000447.

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

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (8)
Drug Metabolism and Disposition
Vol. 49, Issue 8
1 Aug 2021
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Investigation into MAO B–Mediated Formation of CC112273, a Major Circulating Metabolite of Ozanimod, in Humans and Preclinical Species: Stereospecific Oxidative Deamination of (S)-Enantiomer of Indaneamine (RP101075) by MAO B
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Research ArticleArticle

MAO B–Mediated Metabolism of Ozanimod Metabolite RP101075

April Bai, Veerabahu Shanmugasundaram, Julie V. Selkirk, Sekhar Surapaneni and Deepak Dalvie
Drug Metabolism and Disposition August 1, 2021, 49 (8) 601-609; DOI: https://doi.org/10.1124/dmd.121.000447

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Research ArticleArticle

MAO B–Mediated Metabolism of Ozanimod Metabolite RP101075

April Bai, Veerabahu Shanmugasundaram, Julie V. Selkirk, Sekhar Surapaneni and Deepak Dalvie
Drug Metabolism and Disposition August 1, 2021, 49 (8) 601-609; DOI: https://doi.org/10.1124/dmd.121.000447
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