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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Amodiaquine Clearance and Its Metabolism toN-Desethylamodiaquine Is Mediated by CYP2C8: A New High Affinity and Turnover Enzyme-Specific Probe Substrate

Xue-Qing Li, Anders Björkman, Tommy B. Andersson, Marianne Ridderström and Collen M. Masimirembwa
Journal of Pharmacology and Experimental Therapeutics February 2002, 300 (2) 399-407; DOI: https://doi.org/10.1124/jpet.300.2.399
Xue-Qing Li
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Anders Björkman
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Tommy B. Andersson
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Marianne Ridderström
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Collen M. Masimirembwa
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Abstract

Amodiaquine (AQ) metabolism to N-desethylamodiaquine (DEAQ) is the principal route of disposition in humans. Using human liver microsomes and two sets of recombinant human cytochrome P450 isoforms (from lymphoblastoids and yeast) we performed studies to identify the CYP isoform(s) involved in the metabolism of AQ. CYP2C8 was the main hepatic isoform that cleared AQ and catalyzed the formation of DEAQ. The extrahepatic P450s, 1A1 and 1B1, also cleared AQ and catalyzed the formation of an unknown metabolite M2. TheKm and Vmaxvalues for AQ N-desethylation were 1.2 μM and 2.6 pmol/min/pmol of CYP2C8 for recombinant CYP2C8, and 2.4 μM and 1462 pmol/min/mg of protein for human liver microsomes (HLMs), respectively. Relative contribution of CYP2C8 in the formation of DEAQ was estimated at 100% using the relative activity factor method. Correlation analyses between AQ metabolism and the activities of eight hepatic P450s were made on 10 different HLM samples. Both the formation of DEAQ and the clearance of AQ showed excellent correlations (r2 = 0.98 and 0.95) with 6α-hydroxylation of paclitaxel, a marker substrate for CYP2C8. The inhibition of DEAQ formation by quercetin was competitive withKi values of 1.96 for CYP2C8 and 1.56 μM for HLMs. Docking of AQ into the active site homology models of the CYP2C isoforms showed favorable interactions with CYP2C8, which supported the likelihood of an N-desethylation reaction. These data show that CYP2C8 is the main hepatic isoform responsible for the metabolism of AQ. The specificity, high affinity, and high turnover make AQ desethylation an excellent marker reaction for CYP2C8 activity.

Footnotes

  • X.-Q.L. is a recipient of the Wenner-Gren Foundation postdoctoral fellowship (Stockholm, Sweden).

  • Abbreviations:
    AQ
    amodiaquine
    DEAQ
    N-desethylamodiaquine
    bisDEAQ
    N-bisdesethylamodiaquine
    P450
    cytochrome P450
    HLM
    human liver microsome
    RAF
    relative activity factor
    LC
    liquid chromatography
    HPLC
    high-performance LC
    MS
    mass spectroscopy
    tR
    retention time
    • Received July 25, 2001.
    • Accepted October 5, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 300 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 300, Issue 2
1 Feb 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Amodiaquine Clearance and Its Metabolism toN-Desethylamodiaquine Is Mediated by CYP2C8: A New High Affinity and Turnover Enzyme-Specific Probe Substrate

Xue-Qing Li, Anders Björkman, Tommy B. Andersson, Marianne Ridderström and Collen M. Masimirembwa
Journal of Pharmacology and Experimental Therapeutics February 1, 2002, 300 (2) 399-407; DOI: https://doi.org/10.1124/jpet.300.2.399

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Amodiaquine Clearance and Its Metabolism toN-Desethylamodiaquine Is Mediated by CYP2C8: A New High Affinity and Turnover Enzyme-Specific Probe Substrate

Xue-Qing Li, Anders Björkman, Tommy B. Andersson, Marianne Ridderström and Collen M. Masimirembwa
Journal of Pharmacology and Experimental Therapeutics February 1, 2002, 300 (2) 399-407; DOI: https://doi.org/10.1124/jpet.300.2.399
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