Article Figures & Data
Figures
- 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
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
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.
- 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.
- 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
ITZ KTZ AUC (μmol · min/ml) 0.506 ± 0.070 4.36 ± 0.71 CLtot (ml/min/kg) 14.0 ± 1.7 4.40 ± 0.78 T 1/2β (h) 8.78 ± 1.02 1.21 ± 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).
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ITZ KTZ 1 h 4 h Cp (μM) 5.21 ± 0.69 3.42 ± 0.65 6.59 ± 0.95 fp 0.0034 ± 0.0002 0.0095 ± 0.0003 Cpf (μM) 0.0177 ± 0.0023 0.0116 ± 0.0022 0.0626 ± 0.0090 Ch (μM) 92.9 ± 7.4 69.5 ± 9.2 23.4 ± 0.6 fh 0.0024 ± 0.0004 0.0035 ± 0.0006 Chf (μM) 0.223 ± 0.018 0.167 ± 0.022 0.0819 ± 0.0021 Kph 15.4 ± 0.4 20.3 ± 0.3 3.64 ± 0.32 Chf/Cpf 10.9 ± 0.3 14.3 ± 0.2 1.31 ± 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).
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−ITZ +ITZ −KTZ +KTZ AUC (μmol · min/ml) 0.336 ± 0.051 0.719 ± 0.155** 0.291 ± 0.074 0.487 ± 0.052** CLtot (ml/min/kg) 93.3 ± 13.9 44.4 ± 9.4** 111.4 ± 28.5 63.9 ± 6.9* T 1/2β (min) 32.6 ± 0.7 65.2 ± 3.0*** 27.8 ± 3.9 33.4 ± 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).
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- Table 4
Kinetic parameters for metabolism of MDZ and inhibition by ITZ, ITZ-OH, and KTZ in rat microsomes
Metabolism of MDZ Ki Km Vmax μM nmol/mg protein/min μM ITZ 7.16 ± 0.18 2.09 ± 0.02 0.23 ± 0.01 ITZ-OH 7.03 ± 0.46 4.00 ± 0.09 18.2 ± 1.1 KTZ 6.84 ± 0.46 3.92 ± 0.10 0.16 ± 0.01 -
Km, Vmax, andKi represent Michaelis-Menten constant, maximum metabolic reaction velocity, and inhibition constant, respectively. Values are means ± S.D. (n = 3).
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- Table 5
Comparison between predicted value and observed value of increase in ratio of plasma concentration of MDZ
Inhibitor Rp 1 + Cpf/Ki Rh 1 + Chf/Ki R AUC′/AUC ITZ 1.03 ∼ 1.05 1.73 ∼ 1.97 2.14 KTZ 1.39 1.51 1.67 Cimetidine5-a 1.54 2.04 2.5 Nizatidine5-a 1.02 1.05 1.0 -
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.
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↵5-a Cited from our report concerning the interaction between histamine H2 receptor antagonists and MDZ (Takedomi et al., 1998).
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