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Research ArticleArticle

Regioselective Metabolism of Taxoids by Human CYP3A4 and 2C8: Structure-Activity Relationship

Thierry Cresteil, Bernard Monsarrat, Joelle Dubois, Michelle Sonnier, Paul Alvinerie and Françoise Gueritte
Drug Metabolism and Disposition April 2002, 30 (4) 438-445; DOI: https://doi.org/10.1124/dmd.30.4.438
Thierry Cresteil
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Bernard Monsarrat
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Joelle Dubois
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Michelle Sonnier
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Paul Alvinerie
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Françoise Gueritte
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Abstract

Paclitaxel and docetaxel are metabolized by liver microsomal monooxygenases into inactive metabolites further eliminated from the body via the bile route. In spite of their close chemical structure, the two drugs are oxidized by two different enzymes; CYP2C8 catalyzes the 6-hydroxylation on the taxane ring of paclitaxel, whereas CYP3A4 oxidizes docetaxel on the tert-butyl group of the lateral chain in C13. Since paclitaxel and docetaxel differ only by two substitutions, the role of individual modifications was investigated; the regioselectivity of hydroxylation was assessed by high-pressure liquid chromatography/mass spectrometry, and enzymes implicated in individual reactions were identified using human liver microsomes and recombinant P450 expressed in Ad293 cells. The biotransformation of docetaxel, 10-deacetylpaclitaxel, and 10-deacetylbaccatin III was steadily increased (2- to 5-fold) by the addition of an acetyl group in position 10, suggesting that the presence of a hydrophobic group in position 10 stimulated hydroxylation by P450 proteins. The absence of the lateral chain at C13 in baccatin III severely impaired the metabolism supported by CYP3A4. The presence of a tert-butyl group in the lateral chain of docetaxel favored the hydroxylation on the tert-butyl by CYP3A4, whereas the presence of a phenyl group in the lateral chain facilitated the oxidation on the taxane ring by CYP2C8. Collectively, these data strongly suggested that the structure of the lateral chain and the nature of substituent in position 10 play an important role in determining the regioselective oxidation by P450 proteins and modulate the reaction rate by human liver microsomes.

Footnotes

  • This work was supported by Grant 9123 from Association de Recherche sur le Cancer and Grant 99001129 from Conseil régional Midi-Pyrénées.

  • Abbreviations used are::
    P450
    cytochrome P450
    HPLC
    high-pressure liquid chromatography
    MS
    mass spectometry
    • Received October 9, 2001.
    • Accepted January 3, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (4)
Drug Metabolism and Disposition
Vol. 30, Issue 4
1 Apr 2002
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Research ArticleArticle

Regioselective Metabolism of Taxoids by Human CYP3A4 and 2C8: Structure-Activity Relationship

Thierry Cresteil, Bernard Monsarrat, Joelle Dubois, Michelle Sonnier, Paul Alvinerie and Françoise Gueritte
Drug Metabolism and Disposition April 1, 2002, 30 (4) 438-445; DOI: https://doi.org/10.1124/dmd.30.4.438

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Research ArticleArticle

Regioselective Metabolism of Taxoids by Human CYP3A4 and 2C8: Structure-Activity Relationship

Thierry Cresteil, Bernard Monsarrat, Joelle Dubois, Michelle Sonnier, Paul Alvinerie and Françoise Gueritte
Drug Metabolism and Disposition April 1, 2002, 30 (4) 438-445; DOI: https://doi.org/10.1124/dmd.30.4.438
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