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Research ArticleArticle

Interaction of N-(2-Hydroxypropyl)methacrylamide Copolymer-Doxorubicin Conjugates with Human Liver Microsomal Cytochromes P450: Comparison with Free Doxorubicin

Vlastimil Mašek, Eva Anzenbacherová, Tomáš Etrych, Jiří Strohalm, Karel Ulbrich and Pavel Anzenbacher
Drug Metabolism and Disposition September 2011, 39 (9) 1704-1710; DOI: https://doi.org/10.1124/dmd.110.037986
Vlastimil Mašek
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Eva Anzenbacherová
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Tomáš Etrych
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Jiří Strohalm
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Karel Ulbrich
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Pavel Anzenbacher
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Abstract

Interaction of nine forms of human hepatic cytochromes P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) with two N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based doxorubicin (DOX) conjugates designed for passive tumor targeting was studied using pooled human microsomes. The compounds used in this study were two high-molecular-weight HPMA copolymers bearing doxorubicin attached to the polymeric carrier by 1) hydrazone bond enabling intracellular pH-controlled drug release or 2) amide bond through enzymatically cleavable tetrapeptide GlyPheLeuGly spacer. Both polymeric conjugates differing in mechanism of their antitumor activity and the free doxorubicin as the control were tested for potential inhibition activity. Among nine cytochrome P450 forms studied, no HPMA copolymer with bound DOX caused an inhibition of potential clinical significance. The extent of inhibition of enzymatic activities of the cytochrome P450 forms studied was negligible with the exception of CYP2B6 and was apparently caused by DOX as no inhibition was observed with polymers alone, and the extent of inhibition by the complex corresponded to this of the free DOX at the same concentration. In conclusion, the polymers and their conjugates with DOX seem to be relatively safe, at least in this respect, i.e., of inhibition of the liver microsomal drug-metabolizing enzymes.

Footnotes

  • This work was supported by the Czech Academy of Sciences [Grant KAN 200200651]; and the Ministry of Education of Czech Republic [Grant MSM 6198959216]. The infrastructural part of this project (Institute of Molecular and Translational Medicine) was supported by the Operational Programme Research and Development for Innovations [Project CZ.1.05/2.1.00/01.0030].

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

    doi:10.1124/dmd.110.037986.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    HPMA
    N-(2-hydroxypropyl)methacrylamide
    DOX
    doxorubicin
    DOX·HCl
    doxorubicin hydrochloride
    AIBN
    2,2′-azobis(isobutyronitrile)
    DMSO
    dimethyl sulfoxide
    AP
    1-aminopropan-2-ol.

  • Received January 6, 2011.
  • Accepted June 3, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (9)
Drug Metabolism and Disposition
Vol. 39, Issue 9
1 Sep 2011
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Research ArticleArticle

Interaction of N-(2-Hydroxypropyl)methacrylamide Copolymer-Doxorubicin Conjugates with Human Liver Microsomal Cytochromes P450: Comparison with Free Doxorubicin

Vlastimil Mašek, Eva Anzenbacherová, Tomáš Etrych, Jiří Strohalm, Karel Ulbrich and Pavel Anzenbacher
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1704-1710; DOI: https://doi.org/10.1124/dmd.110.037986

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Research ArticleArticle

Interaction of N-(2-Hydroxypropyl)methacrylamide Copolymer-Doxorubicin Conjugates with Human Liver Microsomal Cytochromes P450: Comparison with Free Doxorubicin

Vlastimil Mašek, Eva Anzenbacherová, Tomáš Etrych, Jiří Strohalm, Karel Ulbrich and Pavel Anzenbacher
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1704-1710; DOI: https://doi.org/10.1124/dmd.110.037986
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