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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Mechanistic Studies on Metabolic Interactions between Gemfibrozil and Statins

Thomayant Prueksaritanont, Jamie J. Zhao, Bennett Ma, Brad A. Roadcap, Cuyue Tang, Yue Qiu, Lida Liu, Jiunn H. Lin, Paul G. Pearson and Thomas A. Baillie
Journal of Pharmacology and Experimental Therapeutics June 2002, 301 (3) 1042-1051; DOI: https://doi.org/10.1124/jpet.301.3.1042
Thomayant Prueksaritanont
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Jamie J. Zhao
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Bennett Ma
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Brad A. Roadcap
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Cuyue Tang
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Yue Qiu
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Lida Liu
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Jiunn H. Lin
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Paul G. Pearson
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Thomas A. Baillie
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Abstract

A series of studies were conducted to explore the mechanism of the pharmacokinetic interaction between simvastatin (SV) and gemfibrozil (GFZ) reported recently in human subjects. After administration of a single dose of SV (4 mg/kg p.o.) to dogs pretreated with GFZ (75 mg/kg p.o., twice daily for 5 days), there was an increase (∼4-fold) in systemic exposure to simvastatin hydroxy acid (SVA), but not to SV, similar to the observation in humans. GFZ pretreatment did not increase the ex vivo hydrolysis of SV to SVA in dog plasma. In dog and human liver microsomes, GFZ exerted a minimal inhibitory effect on CYP3A-mediated SVA oxidation, but did inhibit SVA glucuronidation. After i.v. administration of [14C]SVA to dogs, GFZ treatment significantly reduced (2–3-fold) the plasma clearance of SVA and the biliary excretion of SVA glucuronide (together with its cyclization product SV), but not the excretion of a major oxidative metabolite of SVA, consistent with the in vitro findings in dogs. Among six human UGT isozymes tested, UGT1A1 and 1A3 were capable of catalyzing the glucuronidation of both GFZ and SVA. Further studies conducted in human liver microsomes with atorvastatin (AVA) showed that, as with SVA, GFZ was a less potent inhibitor of the CYP3A4-mediated oxidation of this drug than its glucuronidation. However, with cerivastatin (CVA), the glucuronidation as well as the CYP2C8- and CYP3A4-mediated oxidation pathways were much more susceptible to inhibition by GFZ than was observed with SVA or AVA. Collectively, the results of these studies provide metabolic insight into the nature of drug-drug interaction between GFZ and statins, and a possible explanation for the enhanced susceptibility of CVA to interactions with GFZ.

Footnotes

  • This work was conducted at Merck Research Laboratories, West Point, PA.

  • Abbreviations:
    HMG
    3-hydroxy-3-methyglutaryl
    GFZ
    gemfibrozil
    SV
    simvastatin
    LV
    lovastatin
    AUC
    area under plasma concentration-time curve
    SVA
    simvastatin hydroxy acid
    LVA
    lovastatin hydroxy acid
    UGT
    UDP-glucuronosyltransferase
    AVA
    atorvastatin
    CVA
    cerivastatin
    UDPGA
    UDP-glucuronic acid
    HPLC
    high-performance liquid chromatography
    UGT
    UDP glucuronosyltransferase
    LC/MS/MS
    liquid chromatography-tandem mass spectrometry
    RSD
    relative standard deviation
    • Received January 11, 2002.
    • Accepted February 11, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 3
1 Jun 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Mechanistic Studies on Metabolic Interactions between Gemfibrozil and Statins

Thomayant Prueksaritanont, Jamie J. Zhao, Bennett Ma, Brad A. Roadcap, Cuyue Tang, Yue Qiu, Lida Liu, Jiunn H. Lin, Paul G. Pearson and Thomas A. Baillie
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 1042-1051; DOI: https://doi.org/10.1124/jpet.301.3.1042

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Mechanistic Studies on Metabolic Interactions between Gemfibrozil and Statins

Thomayant Prueksaritanont, Jamie J. Zhao, Bennett Ma, Brad A. Roadcap, Cuyue Tang, Yue Qiu, Lida Liu, Jiunn H. Lin, Paul G. Pearson and Thomas A. Baillie
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 1042-1051; DOI: https://doi.org/10.1124/jpet.301.3.1042
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