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Research ArticleArticle

Inhibition Kinetics of Monoclonal Antibodies against Cytochromes P450

Qin Mei, Cuyue Tang, Yuh Lin, Thomas H. Rushmore and Magang Shou
Drug Metabolism and Disposition June 2002, 30 (6) 701-708; DOI: https://doi.org/10.1124/dmd.30.6.701
Qin Mei
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Cuyue Tang
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Yuh Lin
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Thomas H. Rushmore
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Magang Shou
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Abstract

Monoclonal antibodies (MAbs) inhibitory to individual cytochromes P450 (P450s) are of tremendous utility in identification of P450s responsible for the metabolism of a given drug or drug candidate in pharmaceuticals. In the present study, two inhibitory MAbs against CYP2D6 (MAb2D6–50, IgG2b and MAb2D6–184, IgG2a) were developed by hybridoma technology to exhibit their high specificity and potency. The MAbs were further employed to assess the quantitative role (47–93%) of CYP2D6 to the metabolism of bufuralol in human liver microsomes from seven donors. Together with the MAb inhibitory to CYP3A4 as previously reported (Mei et al., 1999), the MAbs were used to study the inhibition kinetics of dextromethorphan O-demethylation (CYP2D6), testosterone 6β-hydroxylation (CYP3A4) and aflatoxin B1 3-hydroxylation (CYP3A4), respectively, with an adequate size of sample measurement. A kinetic model was proposed to fit the experimental observations with three-dimensional nonlinear regression, thereby resulting in a solution of kinetic parameters, i.e.,KI , KS ,Vmax, α, and β (changes inKI or KS andVmax in the presence of the MAb). As a result, dissociation constants (KI ) of the MAbs for the enzymes and the maximal inhibition (β) values for the P450-catalyzed reactions were predicted to have 0.04 to 0.25 μM and ≥94%, respectively. The results have demonstrated that the model can accurately predict the kinetic parameters and provide some insights into the understanding of the mechanism of MAb interaction with P450 enzyme in nature and the applications of the MAbs in qualitative and quantitative identification of P450s involved in drug metabolism.

Footnotes

  • Abbreviations used are::
    P450
    cytochrome P450
    OR
    cytochrome P450 oxidoreductase
    MAb
    monoclonal antibody
    KPi
    potassium phosphate buffer
    ELISA
    enzyme-linked immunosorbent assay
    HPLC
    high-performance liquid chromatography
    LC-MS
    liquid chromatography-mass spectrometry
    RSS
    residual sum of square
    • Received December 21, 2001.
    • Accepted March 5, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (6)
Drug Metabolism and Disposition
Vol. 30, Issue 6
1 Jun 2002
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Research ArticleArticle

Inhibition Kinetics of Monoclonal Antibodies against Cytochromes P450

Qin Mei, Cuyue Tang, Yuh Lin, Thomas H. Rushmore and Magang Shou
Drug Metabolism and Disposition June 1, 2002, 30 (6) 701-708; DOI: https://doi.org/10.1124/dmd.30.6.701

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Research ArticleArticle

Inhibition Kinetics of Monoclonal Antibodies against Cytochromes P450

Qin Mei, Cuyue Tang, Yuh Lin, Thomas H. Rushmore and Magang Shou
Drug Metabolism and Disposition June 1, 2002, 30 (6) 701-708; DOI: https://doi.org/10.1124/dmd.30.6.701
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