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Research ArticleArticle

Effects of Fibrates on Metabolism of Statins in Human Hepatocytes

Thomayant Prueksaritanont, Cuyue Tang, Yue Qiu, Lillian Mu, Raju Subramanian and Jiunn H. Lin
Drug Metabolism and Disposition November 2002, 30 (11) 1280-1287; DOI: https://doi.org/10.1124/dmd.30.11.1280
Thomayant Prueksaritanont
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Cuyue Tang
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Yue Qiu
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Lillian Mu
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Raju Subramanian
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Jiunn H. Lin
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Abstract

This study investigated the metabolic interaction between fibrates and statin hydroxy acids in human hepatocytes. Gemfibrozil (GFZ) modestly affected the formation of β-oxidative products and CYP3A4-mediated oxidative metabolites of simvastatin hydroxy acid (SVA) but markedly inhibited the glucuronidation-mediated lactonization of SVA and the glucuronidation of a β-oxidation product (IC50 ∼50 and 15 μM, respectively). In contrast, fenofibrate had a minimal effect on all the metabolic pathways of SVA. GFZ also significantly inhibited (IC50 ∼50–60 μM) the oxidation of cerivastatin (CVA) and rosuvastatin (RVA), but not of atorvastatin (AVA), while effectively decreasing (IC50 ∼30 to 60 μM) the lactonization of all three statins. As was observed previously with other statin hydroxy acids, RVA underwent significant glucuronidation to form an acyl glucuronide conjugate and lactonization to form RVA lactone in human liver microsomes and by UGT 1A1 and 1A3. While GFZ is not an inhibitor of CYP3A4, it is a competitive inhibitor (Ki = 87 μM) of CYP2C8, a major catalyzing enzyme for CVA oxidation. These results suggest that 1) the pharmacokinetic interaction observed between GFZ and statins was not likely mediated by the inhibitory effect of GFZ on the β-oxidation, but rather by its effect primarily on the glucuronidation and non-CYP3A-mediated oxidation of statin hydroxy acids, and 2) there is a potential difference between fibrates in their ability to affect the pharmacokinetics of statins, and among statins in their susceptibility to metabolic interactions with GFZ in humans.

Footnotes

  • Abbreviations used are::
    GFZ
    gemfibrozil
    CVA
    cerivastatin
    SV
    simvastatin
    SVA
    simvastatin hydroxy acid
    AVA
    atorvastatin
    RVA
    rosuvastatin
    RV
    the lactone form of rosuvastatin
    UDPGA
    UDP-glucuronic acid
    BOA
    2-bromooctanoic acid
    HPLC
    high performance liquid chromatography
    ACN
    acetonitrile
    LC/MS/MS
    liquid chromatography-tandem mass spectrometry
    AV
    the lactone form of atorvastatin
    CV
    the lactone form of cerivastatin
    MS
    mass spectrometry
    UGT
    UDP glucuronyl transferase
    • Received June 18, 2002.
    • Accepted August 14, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (11)
Drug Metabolism and Disposition
Vol. 30, Issue 11
1 Nov 2002
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Research ArticleArticle

Effects of Fibrates on Metabolism of Statins in Human Hepatocytes

Thomayant Prueksaritanont, Cuyue Tang, Yue Qiu, Lillian Mu, Raju Subramanian and Jiunn H. Lin
Drug Metabolism and Disposition November 1, 2002, 30 (11) 1280-1287; DOI: https://doi.org/10.1124/dmd.30.11.1280

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Research ArticleArticle

Effects of Fibrates on Metabolism of Statins in Human Hepatocytes

Thomayant Prueksaritanont, Cuyue Tang, Yue Qiu, Lillian Mu, Raju Subramanian and Jiunn H. Lin
Drug Metabolism and Disposition November 1, 2002, 30 (11) 1280-1287; DOI: https://doi.org/10.1124/dmd.30.11.1280
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