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Research ArticleArticle

Pharmacokinetics and Differential Regulation of Cytochrome P450 Enzymes in Type 1 Allergic Mice

Tadatoshi Tanino, Akira Komada, Koji Ueda, Toru Bando, Yukie Nojiri, Yukari Ueda and Eiichi Sakurai
Drug Metabolism and Disposition December 2016, 44 (12) 1950-1957; DOI: https://doi.org/10.1124/dmd.116.072462
Tadatoshi Tanino
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Akira Komada
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Koji Ueda
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Toru Bando
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Yukie Nojiri
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Yukari Ueda
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Eiichi Sakurai
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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    Fig. 1.

    Total plasma IgE and serum NO levels in type 1 allergic mice. (A) ○, control mice; ●, sensitized mice. Each point represents the mean ± S.D. of 10–15 mice. *P < 0.01 compared with control mice. (B) At 5 and 7 days after the primary sensitization (PS5 and PS7, respectively), the mice were sacrificed. On day 8 after primary sensitization, the mice received the secondary sensitization of OVA. The mice were sacrificed at SS7. Each point represents the mean ± S.D. of 10 mice. *P < 0.01 compared with individual control mice. **P < 0.05 compared with PS5 mice.

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    Fig. 2.

    Changes in hepatic P450 isozyme activities in IgE-mediated allergic mice. □, control mice for PS7 and SS7; ▪▪▪, sensitized mice (PS7 and SS7 mice). Data are expressed as the mean ± S.D. of 4–6 mice. *P < 0.01 compared with each control mice. **P < 0.01 compared with PS7 mice. (A) APAP formed from 10 μM PH after a 5-minute incubation with microsomes (1 mg/ml); (B) 4-OH-TB formed from 800 μM TB after a 30-minute incubation with microsomes (0.5 mg/ml); (C) 1′-OH-BF formed from 2 μM BF after a 5-minute incubation with microsomes (0.4 mg/ml); (D) 6-OH-CHZ formed from 20 μM CHZ after a 5-minute incubation with microsomes (0.5 mg/ml); (E) 1′-OH-MDZ formed from 10 μM MDZ after a 4-minute incubation with microsomes (0.1 mg/ml).

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    Fig. 3.

    Hepatic protein expression of CYP1A2, 2C, 2D, 2E1 and 3A in sensitized mice. The protein expression is expressed in terms of percentage of the control mice (Cont.) on day 7 after i.p. injection of saline, with the control set to 100%. All samples were loaded in triplicate.

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    Fig. 4.

    Plasma concentration-time profiles of PH, APAP, IMP, and CHZ after single intravenous injection. P450 probe substrates were intravenously injected at each dose of 5 mg/kg: (A) PH (CYP1A2 substrate); (B) APAP (CYP1A2 metabolite); (C) IMP (CYP2D substrate); (D) CHZ (CYP2E1 substrate). ○, mice seven days after i.p. injection of saline (control); ●, PS7 mice; ▪▪▪, SS7 mice. Data are expressed as the mean ± S.D. (n = 4–6).

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    Fig. 5.

    Hepatic PH and CHZ concentrations after intravenous injection. (A) parent PH; (B) parent CHZ. Control: mice seven days after i.p. injection of saline. Data are expressed as the mean ± S.D. (n = 4–6). *P < 0.01, significantly different from control mice. ND, not detectable.

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    Fig. 6.

    Inhibitory effect of NO on the activities of hepatic P450 (CYP) isozymes. Hepatic microsomes were preincubated with 1 mM NOC7 or vehicle for 30 minutes at 37°C. Data are expressed as mean ± S.D. (n = 3) of the percentage of P450 isozyme activities in the absence of NOC7. *P < 0.01, significantly different from the vehicle.

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    Fig. 7.

    Changes in microsomal hepatic P450 (CYP) activities in type 1 allergic mice treated with carboxy-PTIO. □, mice without carboxy-PTIO treatment; ▪▪▪, mice with carboxyl-PTIO treatment. Control: seven days after i.p. injection of saline. Data are expressed as the mean ± S.D. (n = 4). *P < 0.01, significantly different from PS7 mice without carboxy-PTIO treatment.

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    TABLE 1

    Pharmacokinetic parameters after single i.v. injection of PH, IMP and CHZ.

    Data are expressed as the mean (n = 4–6).

    Substrate (or Metabolite)ParameterControlSensitization
    PS7SS7
    PHλ (min−1)0.16 ± 0.030.15 ± 0.030.14 ± 0.01
    AUC (μM·min)266.5 ± 79.1183.0 ± 44.8207.2 ± 31.9
    T1/2 (min)4.60 ± 1.274.91 ± 0.814.97 ± 0.37
    CLtot (ml/min/kg)113.4 ± 29.8161.0 ± 35.2137.9 ± 21.7
    Vd (l/kg)0.89 ± 0.261.19 ± 0.410.66 ± 0.24
    APAPAUC (μM·min)375.3 ± 16.9166.1 ± 22.9a216.7 ± 25.6a
    IMPA (nmol/ml)2.59 ± 0.173.91 ± 0.45a3.52 ± 0.73a
    α (min−1)0.033 ± 0.0110.055 ± 0.0070.040 ± 0.009
    B (nmol/ml)1.62 ± 0.312.02 ± 0.851.48 ± 0.18
    β (min−1)0.017 ± 0.0070.031 ± 0.0110.022 ± 0.002
    CLtot (ml/min/kg)157.9 ± 19.5189.0 ± 6.1177.9 ± 14.8
    AUC (μM·min)101.7 ± 13.583.7 ± 2.789.4 ± 7.8
    Vdss (l/kg)b7.04 ± 0.574.47 ± 0.92a4.72 ± 0.64a
    CHZλ (min−1)0.22 ± 0.040.14 ± 0.01a0.11 ± 0.01a
    AUC (μM·min)859.9 ± 124.51145.8 ± 57.6a1134.6 ± 86.9a
    T1/2 (min)3.16 ± 0.474.86 ± 0.29a6.46 ± 0.23a
    CLtot (ml/min/kg)35.1 ± 5.325.8 ± 1.3a25.9 ± 1.8a
    Vd (l/kg)0.13 ± 0.040.18 ± 0.010.20 ± 0.03
    • AUMC, the area under the first moment curve; Vdss, apparent volume of distribution at steady state. T1/2, half-life.

    • ↵a Significantly different from the control mice; * P < 0.05.

    • ↵b Calculated by Vdss = dose × AUMC/(AUC)2.

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Drug Metabolism and Disposition: 44 (12)
Drug Metabolism and Disposition
Vol. 44, Issue 12
1 Dec 2016
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Research ArticleArticle

Pharmacokinetics and P450 Inhibition in Type 1 Allergic Mice

Tadatoshi Tanino, Akira Komada, Koji Ueda, Toru Bando, Yukie Nojiri, Yukari Ueda and Eiichi Sakurai
Drug Metabolism and Disposition December 1, 2016, 44 (12) 1950-1957; DOI: https://doi.org/10.1124/dmd.116.072462

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Research ArticleArticle

Pharmacokinetics and P450 Inhibition in Type 1 Allergic Mice

Tadatoshi Tanino, Akira Komada, Koji Ueda, Toru Bando, Yukie Nojiri, Yukari Ueda and Eiichi Sakurai
Drug Metabolism and Disposition December 1, 2016, 44 (12) 1950-1957; DOI: https://doi.org/10.1124/dmd.116.072462
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