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Research ArticleArticle

Correlation between In Vivo and In Vitro Hepatic Uptake of Metabolic Inhibitors of Cytochrome P-450 in Rats

Katsuhiro Yamano, Koujirou Yamamoto, Hajime Kotaki, Sayuri Takedomi, Hirotami Matsuo, Yasufumi Sawada and Tatsuji Iga
Drug Metabolism and Disposition November 1999, 27 (11) 1225-1231;
Katsuhiro Yamano
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Koujirou Yamamoto
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Hajime Kotaki
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Sayuri Takedomi
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Hirotami Matsuo
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Yasufumi Sawada
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Tatsuji Iga
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Abstract

To predict the degree of accumulation of hepatic metabolic inhibitors in the liver from the in vitro data, we investigated the relationship between cell/medium concentration ratios (C/M ratios) in isolated rat hepatocytes and liver/blood unbound concentration (KBf) after i.v. administration of various metabolic inhibitors such as itraconazole, ketoconazole, verapamil, diltiazem, enoxacin, ciprofloxacin, clarithromycin, cimetidine, and nizatidine. The C/M ratios of itraconazole were ∼6000 and 200 at the concentrations of 0.1 and 10 μg/ml, respectively, and the uptake of ketoconazole and verapamil into the hepatocytes also showed a concentration dependence, although the degree was smaller than that of itraconazole. The uptake of diltiazem, enoxacin, ciprofloxacin, and clarithromycin into the hepatocytes showed linear profiles on concentration dependence. There was an excellent correlation between C/M ratios and KBf values of all nine drugs with a slope of 1. This finding suggested the possibility of predicting drug concentrations in the liver (CH) from C/M ratios, the blood concentrations of drugs (CB) and unbound fraction in blood (fB), which was expressed by CH = (C/M) · CB · fB. It may be possible to predict the drug concentrations in human liver from KBf values estimated with isolated human hepatocytes and concentrations in the blood in a similar manner as in rats.

Footnotes

  • Send reprint requests to: Katsuhiro Yamano, Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 1-6, Kashima 2-chome, Yodogawa-ku, Osaka 532-8514, Japan.

  • Abbreviations used are::
    AUC
    area under the concentration-time curve
    MDZ
    midazolam
    ITZ
    itraconazole
    KTZ
    ketoconazole
    CIM
    cimetidine
    CAM
    clarithromycin
    NIZ
    nizatidine
    C/M
    concentration in cells to concentration in medium ratio
    KBf
    liver concentration to unbound concentration in blood ratio
    ENX
    enoxacin
    CPFX
    ciprofloxacin
    CAM
    clarithromycin
    VER
    verapamil
    DLZ
    diltiazem
    KP
    liver/plasma concentration ratio
    AUCiv
    area under the plasma concentration-time curve after i.v. administration
    AUCpv
    area under the plasma concentration-time curve after intraportal administration
    KB
    real liver/blood concentration ratio
    KB,app
    apparent liver/blood concentration ratio
    QH
    hepatic blood flow rate
    VH
    volume of liver
    fb
    unbound fraction in blood
    fP
    unbound fraction in plasma
    CB
    concentration in blood
    CP
    concentration in plasma
    R
    increasing ratio
    • Received February 16, 1999.
    • Accepted June 15, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (11)
Drug Metabolism and Disposition
Vol. 27, Issue 11
1 Nov 1999
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Research ArticleArticle

Correlation between In Vivo and In Vitro Hepatic Uptake of Metabolic Inhibitors of Cytochrome P-450 in Rats

Katsuhiro Yamano, Koujirou Yamamoto, Hajime Kotaki, Sayuri Takedomi, Hirotami Matsuo, Yasufumi Sawada and Tatsuji Iga
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1225-1231;

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Research ArticleArticle

Correlation between In Vivo and In Vitro Hepatic Uptake of Metabolic Inhibitors of Cytochrome P-450 in Rats

Katsuhiro Yamano, Koujirou Yamamoto, Hajime Kotaki, Sayuri Takedomi, Hirotami Matsuo, Yasufumi Sawada and Tatsuji Iga
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1225-1231;
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