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Research ArticleArticle

Pharmacokinetics, Pharmacodynamics, Metabolism, Distribution, and Excretion of Carfilzomib in Rats

Jinfu Yang, Zhengping Wang, Ying Fang, Jing Jiang, Frances Zhao, Hansen Wong, Mark K. Bennett, Christopher J. Molineaux and Christopher J. Kirk
Drug Metabolism and Disposition October 2011, 39 (10) 1873-1882; DOI: https://doi.org/10.1124/dmd.111.039164
Jinfu Yang
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Zhengping Wang
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Ying Fang
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Jing Jiang
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Frances Zhao
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Hansen Wong
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Mark K. Bennett
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Christopher J. Molineaux
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Christopher J. Kirk
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Abstract

Carfilzomib [(2S)-N-[(S)-1-[(S)-4-methyl-1-[(R)-2-methyloxiran-2-yl]-1-oxopentan-2-ylcarbamoyl]-2-phenylethyl]-2-[(S)-2-(2-morpholinoacetamido)-4-phenylbutanamido]-4-methylpentanamide, also known as PR-171] is a selective, irreversible proteasome inhibitor that has shown encouraging results in clinical trials in multiple myeloma. In this study, the pharmacokinetics, pharmacodynamics, metabolism, distribution, and excretion of carfilzomib in Sprague-Dawley rats were characterized. After intravenous administration, the plasma concentration of carfilzomib declined rapidly in a biphasic manner. Carfilzomib displayed high plasma clearance [195–319 ml/(min · kg)], a short-terminal half-life (5–20 min), and rapid and wide tissue distribution in rats. The exposure to carfilzomib (Cmax and area under the curve) increased dose proportionally from 2 to 4 mg/kg but less than dose proportionally from 4 to 8 mg/kg. The high clearance was mediated predominantly by extrahepatic metabolism through peptidase cleavage and epoxide hydrolysis. Carfilzomib was excreted mainly as metabolites resulting from peptidase cleavage. Carfilzomib and its major metabolites in urine and bile accounted for approximately 26 and 31% of the total dose, respectively, for a total of 57% within 24 h postdose. Despite the high systemic clearance, potent proteasome inhibition was observed in blood and a variety of tissues. Together with rapid and irreversible target binding, the high clearance may provide an advantage in that “unnecessary” exposure to the drug is minimized and potential drug-related side effects may be reduced.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.111.039164.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    CT-L
    chymotrypsin-like
    MM
    multiple myeloma
    CEP-18770
    [(1R)-1-[[(2S,3R)-3-hydroxy-2-[[(6-phenylpyridin-2-yl)carbonyl]amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid
    NPI-0052
    (4R,5S)-4-(2-chloroethyl)-1-((1S)-cyclohex-2-enyl(hydroxy)methyl)-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione
    PR-171 (carfilzomib)
    (2S)-N-[(S)-1-[(S)-4-methyl-1-[(R)-2-methyloxiran-2-yl]-1-oxopentan-2-ylcarbamoyl]-2-phenylethyl]-2-[(S)-2-(2-morpholinoacetamido)-4-phenylbutanamido]-4-methylpentanamide
    PR-054591
    N-[(S)-1-[(S)-1-[(S)-4-methyl-1-[(R)-2-methyloxiran-2-yl]-1-oxopentan-2-ylcarbamoyl]-2-phenylethylcarbamoyl]-3-methylbutyl]-5-(morpholinomethyl)isoxazole-3-carboxamide
    ONX 0912
    (2S)-3-methoxy-2-[(2S)-3-methoxy-2-[(2-methyl-1,3-thiazol-5-yl)formamido] propanamido]-N-[(2S)-1-[(2R)-2-methyloxiran-2-yl]-1-oxo-3-phenylpropan-2-yl]propanamide
    IS
    internal standard
    PK
    pharmacokinetics
    AUC
    area under plasma concentration-time curve
    CL
    plasma clearance
    t1/2
    terminal half-life
    Vss
    volume of distribution at steady state
    LC-MS/MS
    liquid chromatography tandem mass spectrometry
    MRM
    multiple ion reaction monitoring
    AUClast
    area under plasma concentration-time curve calculated to the last measurable concentration
    AUCinf
    area under plasma concentration-time curve extrapolated to infinity
    Css
    steady-state concentration
    RP
    rat plasma
    RU
    rat urine
    RB
    rat bile
    PD
    pharmacodynamics.

  • Received March 4, 2011.
  • Accepted July 12, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (10)
Drug Metabolism and Disposition
Vol. 39, Issue 10
1 Oct 2011
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Research ArticleArticle

PHARMACOKINETICS OF CARFILZOMIB IN RATS

Jinfu Yang, Zhengping Wang, Ying Fang, Jing Jiang, Frances Zhao, Hansen Wong, Mark K. Bennett, Christopher J. Molineaux and Christopher J. Kirk
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1873-1882; DOI: https://doi.org/10.1124/dmd.111.039164

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Research ArticleArticle

PHARMACOKINETICS OF CARFILZOMIB IN RATS

Jinfu Yang, Zhengping Wang, Ying Fang, Jing Jiang, Frances Zhao, Hansen Wong, Mark K. Bennett, Christopher J. Molineaux and Christopher J. Kirk
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1873-1882; DOI: https://doi.org/10.1124/dmd.111.039164
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