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Research ArticleArticle

Quantitative Prediction of Metabolic Inhibition of Midazolam by Itraconazole and Ketoconazole in Rats: Implication of Concentrative Uptake of Inhibitors into Liver

Katsuhiro Yamano, Koujirou Yamamoto, Hajime Kotaki, Yasufumi Sawada and Tatsuji Iga
Drug Metabolism and Disposition March 1999, 27 (3) 395-402;
Katsuhiro Yamano
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Koujirou Yamamoto
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Hajime Kotaki
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Yasufumi Sawada
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Tatsuji Iga
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Abstract

To evaluate the extent of drug-drug interaction concerning metabolic inhibition in the liver quantitatively, we tried to predict the plasma concentration increasing ratio of midazolam (MDZ) by itraconazole (ITZ) or ketoconazole (KTZ) in rats. MDZ was administered at a dose of 10 mg/kg through the portal vein at 60 min after bolus administration of 20 mg/kg ITZ or during 0.33 mg/h/body of KTZ infusion. The ratio values in the area under the plasma concentration curve of MDZ in the presence of ITZ and KTZ was 2.14 and 1.67, respectively. The liver-unbound concentration to plasma-unbound concentration ratios of ITZ and KTZ were 11∼14 and 1.3, respectively, suggesting a concentrative uptake of both drugs into the liver. ITZ and KTZ competitively inhibited the oxidative metabolism of MDZ in rat liver microsomes, and Ki values of ITZ and KTZ were 0.23 μM and 0.16 μM, respectively. We predicted the ratio values of MDZ in the presence of ITZ and KTZ, usingKi values and unbound concentrations of both drugs in the plasma or liver. The predicted ratio values in the presence of ITZ or KTZ calculated by using unbound concentration in the plasma were 1.03∼1.05 and 1.39, whereas those calculated using unbound concentration in the liver were 1.73∼1.97 and 1.51, respectively, which were very close to the observed ratio values. These findings indicated the necessity to consider the concentrative uptake of inhibitors into the liver for the quantitative prediction of the drug-drug interactions concerning metabolic inhibition in the liver.

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::
    MDZ
    midazolam
    ITZ
    itraconazole
    ITZ-OH
    hydroxy itraconazole
    KTZ
    ketoconazole
    CYP
    cytochrome P-450
    AUC
    area under the plasma concentration curve
    Kph
    liver/plasma concentration ratio
    Chf
    unbound concentration in the liver
    Cpf
    unbound concentration in the plasma
    fh
    liver tissue-unbound fraction
    fp
    protein unbound fraction
    • Received June 15, 1998.
    • Accepted December 7, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (3)
Drug Metabolism and Disposition
Vol. 27, Issue 3
1 Mar 1999
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Research ArticleArticle

Quantitative Prediction of Metabolic Inhibition of Midazolam by Itraconazole and Ketoconazole in Rats: Implication of Concentrative Uptake of Inhibitors into Liver

Katsuhiro Yamano, Koujirou Yamamoto, Hajime Kotaki, Yasufumi Sawada and Tatsuji Iga
Drug Metabolism and Disposition March 1, 1999, 27 (3) 395-402;

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Research ArticleArticle

Quantitative Prediction of Metabolic Inhibition of Midazolam by Itraconazole and Ketoconazole in Rats: Implication of Concentrative Uptake of Inhibitors into Liver

Katsuhiro Yamano, Koujirou Yamamoto, Hajime Kotaki, Yasufumi Sawada and Tatsuji Iga
Drug Metabolism and Disposition March 1, 1999, 27 (3) 395-402;
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