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Research ArticleArticle

CYP2C8 Activity Recovers within 96 Hours after Gemfibrozil Dosing: Estimation of CYP2C8 Half-Life Using Repaglinide as an in Vivo Probe

Janne T. Backman, Johanna Honkalammi, Mikko Neuvonen, Kaisa J. Kurkinen, Aleksi Tornio, Mikko Niemi and Pertti J. Neuvonen
Drug Metabolism and Disposition December 2009, 37 (12) 2359-2366; DOI: https://doi.org/10.1124/dmd.109.029728
Janne T. Backman
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Johanna Honkalammi
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Mikko Neuvonen
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Kaisa J. Kurkinen
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Aleksi Tornio
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Mikko Niemi
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Pertti J. Neuvonen
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Abstract

Gemfibrozil 1-O-β-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8. We studied the recovery of CYP2C8 activity after discontinuation of gemfibrozil treatment using repaglinide as a probe drug, to estimate the in vivo turnover half-life of CYP2C8. In a randomized five-phase crossover study, nine healthy volunteers ingested 0.25 mg of repaglinide alone or after different time intervals after a 3-day treatment with 600 mg of gemfibrozil twice daily. The area under the plasma concentration-time curve (AUC) from time 0 to infinity of repaglinide was 7.6-, 2.9-, 1.4- and 1.0-fold compared with the control phase when it was administered 1, 24, 48, or 96 h after the last gemfibrozil dose, respectively (P < 0.001 versus control for 1, 24, and 48 h after gemfibrozil). Thus, a strong CYP2C8 inhibitory effect persisted even after gemfibrozil and gemfibrozil 1-O-β-glucuronide concentrations had decreased to less than 1% of their maximum (24-h dosing interval). In addition, the metabolite to repaglinide AUC ratios indicated that significant (P < 0.05) inhibition of repaglinide metabolism continued up to 48 h after gemfibrozil administration. Based on the recovery of repaglinide oral clearance, the in vivo turnover half-life of CYP2C8 was estimated to average 22 ± 6 h (mean ± S.D.). In summary, CYP2C8 activity is recovered gradually during days 1 to 4 after gemfibrozil discontinuation, which should be considered when CYP2C8 substrate dosing is planned. The estimated CYP2C8 half-life will be useful for in vitro-in vivo extrapolations of drug-drug interactions involving induction or mechanism-based inhibition of CYP2C8.

Footnotes

  • This study was supported by the Helsinki University Central Hospital Research Fund; and the Sigrid Jusélius Foundation, Finland.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.109.029728

  • P450
    cytochrome P450
    OATP
    organic anion transporting polypeptide
    AUC
    area under the concentration-time curve
    CV
    coefficient of variation
    Cmax
    peak concentration
    t1/2
    (elimination) half-life
    ke
    elimination rate constant
    CL/F
    oral clearance
    C0
    concentration at time 0
    tmax
    time to peak concentration
    FDCL
    fractional decrement in the oral clearance.

    • Received July 30, 2009.
    • Accepted September 21, 2009.
  • Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (12)
Drug Metabolism and Disposition
Vol. 37, Issue 12
1 Dec 2009
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Research ArticleArticle

CYP2C8 Activity Recovers within 96 Hours after Gemfibrozil Dosing: Estimation of CYP2C8 Half-Life Using Repaglinide as an in Vivo Probe

Janne T. Backman, Johanna Honkalammi, Mikko Neuvonen, Kaisa J. Kurkinen, Aleksi Tornio, Mikko Niemi and Pertti J. Neuvonen
Drug Metabolism and Disposition December 1, 2009, 37 (12) 2359-2366; DOI: https://doi.org/10.1124/dmd.109.029728

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Research ArticleArticle

CYP2C8 Activity Recovers within 96 Hours after Gemfibrozil Dosing: Estimation of CYP2C8 Half-Life Using Repaglinide as an in Vivo Probe

Janne T. Backman, Johanna Honkalammi, Mikko Neuvonen, Kaisa J. Kurkinen, Aleksi Tornio, Mikko Niemi and Pertti J. Neuvonen
Drug Metabolism and Disposition December 1, 2009, 37 (12) 2359-2366; DOI: https://doi.org/10.1124/dmd.109.029728
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