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Research ArticleArticle

Application of Higher Throughput Screening (HTS) Inhibition Assays to Evaluate the Interaction of Antiparasitic Drugs with Cytochrome P450s

Tashinga E. Bapiro, Ann-Charlotte Egnell, Julia A. Hasler and Collen M. Masimirembwa
Drug Metabolism and Disposition January 2001, 29 (1) 30-35;
Tashinga E. Bapiro
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Ann-Charlotte Egnell
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Julia A. Hasler
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Collen M. Masimirembwa
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Abstract

In this study we have evaluated the application and reliability of using fluorescence (FLUO)-based high throughput screening assays with recombinant CYPs (rCYP). This was accomplished by screening 29 clinically important antiparasitic drugs for inhibition of the five major drug-metabolizing CYPs (-1A2, -2C9, -2C19, -2D6, and -3A4). Data from FLUO/rCYP assays were compared with that obtained by conventional HPLC assays using human liver microsomes (HLM) and rCYPs. TheKi values showed good correlations: FLUO/rCYP and HPLC/rCYP (r2 = 0.81), HPLC/rCYP and HPLC/HLM (r2 = 0.82), and FLUO/rCYP and HPLC/HLM (r2 = 0.72). Niclosamide had substrate-dependent contrasting effects on CYP2C9 activity with an apparent activation (400%) of 7-methoxy-4-trifluoromethylcoumarin demethylase activity and potent inhibition (Ki = 6.00 μM) of diclofenac 4-hydroxylase activity. Potent inhibitors of CYP1A2 were artemisinin, dihydroartemisinin, thiabendazole, primaquine, and niclosamide (Ki = 0.43, 3.67, 1.54, 0.22, and 2.70 μM, respectively). Proguanil, cycloguanil, amodiaquine, and desethylamodiaquine inhibited CYP2D6 (Ki = 6.76, 5.97, 2.1, and 4.13 μM, respectively). Considering the Cmax of these drugs, artemisinin, thiabendazole, primaquine, amodiaquine, and desethylamodiaquine may cause clinically important interactions because they are predicted to inhibit 67 to 99% of the activities of the CYPs they interact with. In addition, our results suggest CYP1A2 inhibition as the mechanism behind the observed thiabendazole/theophylline and primaquine/antipyrine interactions in vivo.

Footnotes

  • Send reprint requests to: Dr. Collen Mutowembwa Masimirembwa, Department of DMPK and Bioanalytical Chemistry, AstraZeneca, R & D Mölndal, S-431 83 Mölndal, Sweden. E-mail: collen.masimirembwa{at}astrazeneca.com

  • Tashinga Bapiro is a recipient of a fellowship from International Programme in Chemical Sciences, Uppsala University, Sweden.

  • Abbreviations used are::
    CYP cytochrome P450
    HPLC, high-performance liquid chromatography
    HTS
    high throughput screening
    rCYP
    recombinant cytochrome P450
    FLUO
    fluorescence
    HLM
    human liver microsome
    MFC
    7-methoxy-4-trifluoromethylcoumarin
    • Received June 30, 2000.
    • Accepted October 17, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (1)
Drug Metabolism and Disposition
Vol. 29, Issue 1
1 Jan 2001
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Research ArticleArticle

Application of Higher Throughput Screening (HTS) Inhibition Assays to Evaluate the Interaction of Antiparasitic Drugs with Cytochrome P450s

Tashinga E. Bapiro, Ann-Charlotte Egnell, Julia A. Hasler and Collen M. Masimirembwa
Drug Metabolism and Disposition January 1, 2001, 29 (1) 30-35;

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Research ArticleArticle

Application of Higher Throughput Screening (HTS) Inhibition Assays to Evaluate the Interaction of Antiparasitic Drugs with Cytochrome P450s

Tashinga E. Bapiro, Ann-Charlotte Egnell, Julia A. Hasler and Collen M. Masimirembwa
Drug Metabolism and Disposition January 1, 2001, 29 (1) 30-35;
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