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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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  • Figure 1
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    Figure 1

    Plasma and liver concentration profiles of ITZ (A) and KTZ (B) after bolus injection of ITZ or KTZ to rats.

    ITZ was administered through the femoral vein at a dose of 5 mg/kg. KTZ was administered through the femoral vein at a dose of 10 mg/kg. Each point represents the mean ± S.D. (n = 3). ●, plasma concentration; ■, liver concentration.

  • Figure 2
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    Figure 2

    Concentration dependency of liver/plasma concentration ratio (KpH) of ITZ (A) and KTZ (B).

    Horizontal line and shaded area represent the mean ± S.D.

  • Figure 3
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    Figure 3

    Effect of ITZ (A) and KTZ (B) on plasma concentration of MDZ.

    A, ITZ was administered through the femoral vein at a dose of 20 mg/kg. MDZ was administered through the portal vein at a dose of 10 mg/kg at 60 min after administration of ITZ. Each point represents the mean ± S.D. (n = 4). ■, plasma concentration of MDZ alone; ●, plasma concentration of MDZ in the presence of ITZ; ▴, plasma concentration of ITZ. B, KTZ was administered through the femoral vein at a dose of 5 mg/kg and then infused into the rat at constant rate of 0.33 mg/h/body using a syringe infusion pump. MDZ was administered through the portal vein at a dose of 10 mg/kg at 120 min after the beginning of infusion. Each point represents the mean ± S.D. (n = 4). ■, plasma concentration of MDZ alone; ●, plasma concentration of MDZ in the presence of KTZ; ▴, plasma concentration of KTZ.

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    Figure 4

    The inhibitory effect of ITZ (A), KTZ (B), and ITZ-OH (C) on the metabolism of MDZ by rat liver microsomes based on a Lineweaver-Burk plot.

    The concentrations of MDZ in inhibition of metabolism were 1, 2, 5, 10, and 20 μM, and the concentrations of inhibitors were ITZ: 0.1, 0.2, 0.5, and 1 μM; KTZ: 0.1, 0.2, 0.5, and 1 μM; ITZ-OH: 10, 20, and 50 μM. A and B: ○, MDZ alone; ●, with 0.1 μM ITZ, KTZ; ■, with 0.2 μM ITZ, KTZ; ▴, with 0.5 μM ITZ, KTZ; ⧫, with 1 μM ITZ, KTZ. C: ○, MDZ alone; ●, with 10 μM ITZ-OH; ■, with 20 μM ITZ-OH; ▴, with 50 μM ITZ-OH.

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    Figure 5

    The effect of temperature and metabolic inhibitor on the initial uptake rates of ITZ (A) and KTZ (B) into rat hepatocytes.

    Each point represents the mean ± S.D. (n = 4).

Tables

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    Table 1

    Pharmacokinetic parameters of ITZ and KTZ in rats

    ITZKTZ
    AUC (μmol · min/ml)0.506  ± 0.0704.36  ± 0.71
    CLtot (ml/min/kg)14.0  ± 1.74.40  ± 0.78
    T 1/2β (h)8.78  ± 1.021.21  ± 0.10
    • AUC, CLtot, and T1/2β are area under the plasma concentration curve, total body clearance, and half-life in β phase, respectively. Values are means ± S.D. (n = 3).

    • View popup
    Table 2

    Liver and plasma concentrations of ITZ and KTZ in rats

    ITZKTZ
    1 h4 h
    Cp (μM)5.21  ± 0.693.42  ± 0.656.59  ± 0.95
    fp0.0034 ± 0.00020.0095  ± 0.0003
    Cpf (μM)0.0177  ± 0.00230.0116  ± 0.00220.0626  ± 0.0090
    Ch (μM)92.9  ± 7.469.5  ± 9.223.4  ± 0.6
    fh 0.0024 ± 0.00040.0035  ± 0.0006
    Chf (μM)0.223  ± 0.0180.167  ± 0.0220.0819  ± 0.0021
    Kph 15.4  ± 0.420.3  ± 0.33.64  ± 0.32
    Chf/Cpf10.9  ± 0.314.3  ± 0.21.31  ± 0.12
    • Cp, fp, Cpf, Ch, fH, Chf, and Kph are concentration in the plasma, unbound fraction in the plasma, unbound concentration in the plasma, concentration in the liver, unbound fraction in the liver, unbound concentration in the liver, and liver to plasma concentration ratio, respectively. Values are means ± S.D. (n = 3–4).

    • View popup
    Table 3

    Pharmacokinetic parameters of MDZ in the absence or the presence of ITZ and KTZ

    −ITZ+ITZ−KTZ+KTZ
    AUC (μmol · min/ml)0.336  ± 0.0510.719  ± 0.155** 0.291  ± 0.0740.487  ± 0.052**
    CLtot (ml/min/kg)93.3  ± 13.944.4  ± 9.4** 111.4  ± 28.563.9  ± 6.9*
    T 1/2β (min)32.6  ± 0.765.2  ± 3.0*** 27.8  ± 3.933.4  ± 1.0*
    • AUC, CLtot, and T1/2β are area under the plasma concentration curve, total body clearance, and half life in β phase, respectively. Values are means ± S.D. (n = 4). Significant differences from −ITZ or −KTZ were determined by Student’s t test (* p< .05, ** p < .01, *** p < .001).

    • View popup
    Table 4

    Kinetic parameters for metabolism of MDZ and inhibition by ITZ, ITZ-OH, and KTZ in rat microsomes

    Metabolism of MDZKi
    KmVmax
    μM nmol/mg protein/min μM
    ITZ7.16  ± 0.182.09  ± 0.020.23  ± 0.01
    ITZ-OH7.03  ± 0.464.00  ± 0.0918.2  ± 1.1
    KTZ6.84  ± 0.463.92  ± 0.100.16  ± 0.01
    • Km, Vmax, andKi represent Michaelis-Menten constant, maximum metabolic reaction velocity, and inhibition constant, respectively. Values are means ± S.D. (n = 3).

    • View popup
    Table 5

    Comparison between predicted value and observed value of increase in ratio of plasma concentration of MDZ

    InhibitorRp 1 + Cpf/KiRh 1 + Chf/KiR AUC′/AUC
    ITZ1.03 ∼ 1.051.73 ∼ 1.972.14
    KTZ1.391.511.67
    Cimetidine5-a 1.542.042.5
    Nizatidine5-a 1.021.051.0
    • The increase ratios, Rp, and RH were calculated from Cpf using eq. 19 and CHf using eq. 17. AUC′/AUC is observed value calculated from Fig. 3.

    • ↵5-a Cited from our report concerning the interaction between histamine H2 receptor antagonists and MDZ (Takedomi et al., 1998).

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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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