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Research ArticleArticle

Prediction of Hepatic Clearance and Availability by Cryopreserved Human Hepatocytes: An Application of Serum Incubation Method

Yoshihiro Shibata, Hiroyuki Takahashi, Masato Chiba and Yasuyuki Ishii
Drug Metabolism and Disposition August 2002, 30 (8) 892-896; DOI: https://doi.org/10.1124/dmd.30.8.892
Yoshihiro Shibata
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Hiroyuki Takahashi
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Masato Chiba
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Yasuyuki Ishii
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Abstract

A novel and convenient method was established for the prediction of in vivo metabolic clearance in human liver. The present method applied the in vitro-in vivo extrapolation paradigm previously established in rats to the in vitro data obtained from cryopreserved human hepatocytes. Predicted hepatic availability and clearance were compared with the reported oral bioavailability and plasma clearance in humans for 14 clinically used drugs (naloxone, buspirone, verapamil, lidocaine, imipramine, metoprolol, timolol, antipyrine, diazepam, quinidine, caffeine, propranolol, diclofenac, and phenacetin). A large interindividual variation was observed in the intrinsic metabolic clearance among separate cryopreserved preparations from different subjects. The prediction generally resulted in a marked underestimation when the biologically based scaling factor (3.1 × 109cells/kg) was used for the extrapolation of in vitro data (milliliters per minutes per cells) to in vivo value (milliliters per minutes per kilograms). Reasonably good in vitro-in vivo correlations were obtained with empirically calculated scaling factors, 8.5 × 109 (cells/kg) from 10 individual preparations and 10.8 × 109 (cells/kg) from pooled preparation of two selected lots, which were 3- to 4-fold larger than the biologically based scaling factor. These data suggested that the calibration of inherent interindividual variation of metabolic activities among different cryopreserved preparations of human hepatocytes to obtain the empirical scaling factor, which is applicable only to the preparation used, was an essential step for more reliable and quantitative prediction of in vivo metabolic activity in humans.

Footnotes

  • Abbreviations used are::
    HPLC
    high-performance liquid chromatography
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    CLint, in vitro
    in vitro intrinsic clearance observed when test compounds were metabolized by human hepatocytes suspended in human serum
    D
    cell density of hepatocytes suspended in serum
    T
    incubation time
    R
    ratio of intact drug concentration after incubation to that at time 0
    SF70+73
    scaling factor calculated from CLint, in vitro, 70+73/CLH, int, in vivo for the pooled hepatocyte preparation of lot 70 and 73
    CLH, int, in vitro, 70+73
    hepatic intrinsic clearance calculated from in vitro data using the pooled hepatocyte preparation of lot 70 and 73
    CLint, in vitro, 70+73
    in vitro intrinsic clearance observed when test compounds were metabolized in the pooled hepatocyte preparation of lot 70 and 73 suspended in human serum
    FH
    hepatic availability
    CLH, predicted, 70+73
    predicted hepatic clearance from CLint, in vitro, 70+73 and average SF70+73
    QH
    hepatic blood flow rate
    RB
    blood-to-plasma concentration ratio
    DN
    dispersion number
    CLP, in vivo
    in vivo plasma clearance
    FPO, in vivo
    oral bioavailability in humans
    CLH, int, in vivo
    hepatic intrinsic clearance calculated from FPO, in vivoby the dispersion model (using the Goal Seek method attached to Microsoft Excel)
    SFmean
    mean of scaling factor calculated from CLint, in vitro, mean/CLH, int, in vivo for 10 individual lots
    average SFmean
    average value of SFmean for seven standard compounds
    FH, predicted, 70+73
    predicted hepatic availability from CLint, in vitro, 70+73 and average SF70+73
    SFbiol
    biologically based scaling factor of hepatocellularity (3.1×109 cells/kg)
    average SF70+73
    average value of SF70+73 for seven standard compounds
    • Received December 13, 2001.
    • Accepted April 24, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (8)
Drug Metabolism and Disposition
Vol. 30, Issue 8
1 Aug 2002
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Research ArticleArticle

Prediction of Hepatic Clearance and Availability by Cryopreserved Human Hepatocytes: An Application of Serum Incubation Method

Yoshihiro Shibata, Hiroyuki Takahashi, Masato Chiba and Yasuyuki Ishii
Drug Metabolism and Disposition August 1, 2002, 30 (8) 892-896; DOI: https://doi.org/10.1124/dmd.30.8.892

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Research ArticleArticle

Prediction of Hepatic Clearance and Availability by Cryopreserved Human Hepatocytes: An Application of Serum Incubation Method

Yoshihiro Shibata, Hiroyuki Takahashi, Masato Chiba and Yasuyuki Ishii
Drug Metabolism and Disposition August 1, 2002, 30 (8) 892-896; DOI: https://doi.org/10.1124/dmd.30.8.892
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