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Research ArticleArticle

Inhibition of CYP3A4 in a Rapid Microtiter Plate Assay Using Recombinant Enzyme and in Human Liver Microsomes Using Conventional Substrates

Amin A. Nomeir, Charles Ruegg, Matthew Shoemaker, Leonard V. Favreau, Jairam R. Palamanda, Paul Silber and Chin-chung Lin
Drug Metabolism and Disposition May 2001, 29 (5) 748-753;
Amin A. Nomeir
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Charles Ruegg
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Matthew Shoemaker
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Leonard V. Favreau
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Jairam R. Palamanda
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Paul Silber
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Chin-chung Lin
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Abstract

Cytochrome P450 inhibition studies are performed in the pharmaceutical industry in the discovery stage to screen candidates that may have the potential for clinical drug-drug interactions. A 96-well microtiter plate assay using recombinant cytochrome P450 (Supersomes) has been used to increase the overall throughput. The IC50 values for the inhibition of CYP3A4 by 52 new chemical entities (NCEs) were determined using the Supersomes assay with resorufin benzyl ether as a substrate, and the data were compared with those obtained in human liver microsomes (HLM) using midazolam as a substrate. Among the 52 compounds tested, 25 showed IC50values within a 5-fold difference in the two assays. For all compounds that showed a >5-fold difference, the IC50 values in the Supersomes assay were lower than those obtained in HLM, except for one compound. Further studies suggested that this discrepancy was not related to difference in protein concentrations between the two assays. In addition, the IC50 values for 16 compounds with a wide range of inhibition potency were determined in HLM using testosterone and dextromethorphan as substrates. The results showed an 80 to 93% match within a 5-fold difference between the three probe substrates. However, for certain compounds including ketoconazole, there were substrate-dependent differences in the inhibition. The results suggest that the difference between the Supersomes and HLM could be partially attributed to differences in the substrate used, and to metabolism by other cytochrome P450s present in the HLM but not in the Supersomes. Furthermore, multiple CYP3A4 substrates should be used to improve the reliability of estimating potential drug-drug interaction of NCEs.

Footnotes

  • Send reprint requests to: Amin A. Nomeir, Ph.D., Director, Exploratory Drug Metabolism, Department of Drug Metabolism and Pharmacokinetics, Mail Stop 2880, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033. E-mail:amin.nomeir{at}spcorp.com

  • Abbreviations used are::
    HLM
    human liver microsomes
    NCE
    new chemical entity
    NRS
    NADPH-regenerating system
    TAO
    troleandomycin
    HPLC
    high-performance liquid chromatography
    P450
    cytochrome P450
    • Received October 3, 2000.
    • Accepted February 2, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (5)
Drug Metabolism and Disposition
Vol. 29, Issue 5
1 May 2001
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Research ArticleArticle

Inhibition of CYP3A4 in a Rapid Microtiter Plate Assay Using Recombinant Enzyme and in Human Liver Microsomes Using Conventional Substrates

Amin A. Nomeir, Charles Ruegg, Matthew Shoemaker, Leonard V. Favreau, Jairam R. Palamanda, Paul Silber and Chin-chung Lin
Drug Metabolism and Disposition May 1, 2001, 29 (5) 748-753;

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Research ArticleArticle

Inhibition of CYP3A4 in a Rapid Microtiter Plate Assay Using Recombinant Enzyme and in Human Liver Microsomes Using Conventional Substrates

Amin A. Nomeir, Charles Ruegg, Matthew Shoemaker, Leonard V. Favreau, Jairam R. Palamanda, Paul Silber and Chin-chung Lin
Drug Metabolism and Disposition May 1, 2001, 29 (5) 748-753;
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