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Research ArticleArticle

A Convenient In Vitro Screening Method for Predicting In Vivo Drug Metabolic Clearance Using Isolated Hepatocytes Suspended in Serum

Yoshihiro Shibata, Hiroyuki Takahashi and Yasuyuki Ishii
Drug Metabolism and Disposition December 2000, 28 (12) 1518-1523;
Yoshihiro Shibata
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Hiroyuki Takahashi
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Yasuyuki Ishii
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Abstract

A novel and convenient in vitro method for predicting in vivo metabolic clearance in the liver (CLH) was developed. The CLH of a drug is usually predicted by using both the unbound fraction in serum and the intrinsic hepatic clearance of the unbound fraction, but this procedure is labor-intensive. We simplified the method by directly measuring intrinsic hepatic clearance using isolated rat hepatocytes suspended in rat serum and called this “the serum incubation method”. Sixteen commercially available compounds reported to be mainly excreted by liver metabolism were evaluated using our method. The remaining ratio of the unchanged drug after incubation was measured to calculate the rate of metabolism, and then CLH was predicted based on the dispersion model. The predicted CLH values of the drugs estimated by the serum incubation method were in good agreement with their in vivo plasma clearance values. In addition, the intrinsic hepatic clearance values obtained by the serum incubation method were comparable with those obtained by conventional methods. Furthermore, oral bioavailability values were equal to or lower than hepatic availability values predicted from the serum incubation method. These results indicate that compounds showing poor oral bioavailability can be excluded before in vivo pharmacokinetic study by using this method. In conclusion, the serum incubation method is a convenient and useful tool at the early stage of drug discovery.

Footnotes

  • Send reprint requests to: Yoshihiro Shibata, Drug Metabolism, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Techno-park Oho, Tsukuba, Ibaraki 300-2611, Japan.

  • Abbreviations used are::
    fub
    unbound fraction in serum
    CL
    clearance
    CLu int, WE
    intrinsic clearance of unbound fraction obtained from incubation in WE
    CLint, serum
    intrinsic clearance obtained from incubation in serum
    CLH
    hepatic clearance
    CLH, u int
    hepatic intrinsic clearance of unbound fraction
    CLH, u int, WE
    hepatic intrinsic clearance of unbound fraction obtained from incubation in WE
    CLH, int
    hepatic intrinsic clearance
    CLH, int, WE
    hepatic intrinsic clearance obtained from incubation in WE
    CLH, int, serum
    hepatic intrinsic clearance obtained from incubation in serum
    CLp
    plasma clearance
    DMSO
    dimethyl sulfoxide
    DN
    dispersion number
    EH
    hepatic extraction ratio
    FH
    hepatic availability
    Fpo
    oral bioavailability
    SF
    scaling factor
    QH
    hepatic blood flow rate
    R
    ratio of intact drug remaining after incubation
    RB
    blood to plasma concentration ratio
    WE
    William's E medium (pH 7.4)
    • Received April 29, 2000.
    • Accepted September 14, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (12)
Drug Metabolism and Disposition
Vol. 28, Issue 12
1 Dec 2000
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Research ArticleArticle

A Convenient In Vitro Screening Method for Predicting In Vivo Drug Metabolic Clearance Using Isolated Hepatocytes Suspended in Serum

Yoshihiro Shibata, Hiroyuki Takahashi and Yasuyuki Ishii
Drug Metabolism and Disposition December 1, 2000, 28 (12) 1518-1523;

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Research ArticleArticle

A Convenient In Vitro Screening Method for Predicting In Vivo Drug Metabolic Clearance Using Isolated Hepatocytes Suspended in Serum

Yoshihiro Shibata, Hiroyuki Takahashi and Yasuyuki Ishii
Drug Metabolism and Disposition December 1, 2000, 28 (12) 1518-1523;
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