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Research ArticleArticle

Stereoselective Pharmacokinetics and Chiral Inversion of Ibuprofen in Adjuvant-induced Arthritic Rats

Hiroyuki Ikuta, Atsushi Kawase and Masahiro Iwaki
Drug Metabolism and Disposition March 2017, 45 (3) 316-324; DOI: https://doi.org/10.1124/dmd.116.073239

Article Figures & Data

Figures

  • Fig. 1.
    Fig. 1.

    A pharmacokinetic model with unidirectional inversion from R-IB to S-IB.

  • Fig. 2.
    Fig. 2.

    Plasma concentration-time profiles of IB enantiomers after intravenous administration of rac-IB (20 mg/kg) in control and AA rats.△, R-IB; ○, S-IB in control rat; ▴, R-IB; ●, S-IB in AA rats. Solid lines represent the fitting curves using the pharmacokinetic model shown in Fig. 1. Results are expressed as the mean ± S.D. (n = 3).

  • Fig. 3.
    Fig. 3.

    Plasma concentration-time profiles of IB enantiomers after intravenous administration of S-IB (10 mg/kg) (A) or R-IB (10 mg/kg) (B) in control and AA rats. △, R-IB; ○, S-IB in control rat; ▴, R-IB; ●, S-IB in AA rats. Solid lines represent the fitting curves using the pharmacokinetic model shown in Fig. 1. Results are expressed as the mean ± S.D. (n = 3).

  • Fig. 4.
    Fig. 4.

    Relative protein levels of ACS1 and APCE in hepatic microsomes of control and AA rats. Results are expressed as the mean ± S.D. (n = 5 or 6). Significant differences between control and AA rats are indicated. ***P < 0.001.

  • Fig. 5.
    Fig. 5.

    Effects of AA induction on CLRS (ml/min/kg) and CLMET (ml/min/kg) of IB. Chiral centers indicated by an asterisk.

Tables

  • TABLE 1

    Noncompartmental pharmacokinetic parameters of each enantiomer after intravenous administration of rac-IB

    Results are expressed as the mean ± SD (n = 3).

    ParameterControlAA
    R-IBS-IBR-IBS-IB
    T1/2 (min)35.7 ± 6.889.5 ± 37.130.7 ± 6.569.0 ± 17.0b
    CLtot (ml/min/kg)3.70 ± 0.140.80 ± 0.27b5.40 ± 0.71a1.20 ± 0.31b
    MRT (min)32.7 ± 3.9127 ± 51.9b30.3 ± 5.797.5 ± 29.5b
    Vdss (ml/kg)120 ± 1889 ± 10165 ± 38115 ± 21
    AUC0-∞ (μg∣min/ml)2720 ± 10314031 ± 4496b1862 ± 230a8597 ± 2350b

    • ↵a P < 0.05 compared with controls.

    • ↵b P < 0.05 compared with its antipode.

  • TABLE 2

    Compartmental pharmacokinetic parameters of each enantiomer after intravenous administration of rac-IB

    Results are expressed as the mean ± S.D. (n = 3).

    ParameterControlAA
    R-IBS-IBR-IBS-IB
    V1 (ml/kg)63.1 ± 4.467.3 ± 9.986.0 ± 34.295.8 ± 18.3
    V2 (ml/kg)56.4 ± 24.656.0 ± 23.280.3 ± 28.468.3 ± 29.9
    CLtot (ml/min/kg)4.01 ± 0.401.46 ± 0.40b6.16 ± 1.11a2.19 ± 0.67b
    CLRS (ml/min/kg)2.75 ± 0.39―3.96 ± 0.67a―
    CLMET (ml/min/kg)1.26 ± 0.091.46 ± 0.402.19 ± 0.55a2.19 ± 0.67
    k0(R) (min−1)0.020 ± 0.001―0.024 ± 0.007―
    k12 (min−1)0.072 ± 0.0310.070 ± 0.0350.059 ± 0.0300.070 ± 0.035
    k21 (min−1)0.074 ± 0.0240.062 ± 0.0200.076 ± 0.0190.083 ± 0.018
    k10 (min−1)0.064 ± 0.0070.021 ± 0.003b0.076 ± 0.0170.023 ± 0.004b
    kRS (min−1)0.044 ± 0.007―0.052 ± 0.022―

    • ↵a P < 0.05 compared with controls.

    • ↵b P < 0.05 compared with its antipode.

    • The em dashes indicate no value because of unidirectional chiral inversion of IB.

  • TABLE 3

    Noncompartmental pharmacokinetic parameters of each enantiomer after intravenous administration of R-IB or S-IB

    Results are expressed as the mean ± S.D. (n = 3).

    ParameterControlAA
    R-IB after R-IBS-IB after R-IBS-IB after S-IBR-IB after R-IBS-IB after R-IBS-IB after S-IB
    T1/2 (min)33.9 ± 4.577.8 ± 24.484.2 ± 23.7b30.4 ± 5.069.8 ± 23.956.3 ± 4.8b
    CLtot (ml/kg)4.20 ± 0.23―1.30 ± 0.18b6.20 ± 0.66a―2.40 ± 0.40a,b
    MRT (min)32.8 ± 5.4―109.3 ± 30.5b26.7 ± 3.1―69.6 ± 8.77a,b
    Vdss (ml/kg)137 ± 18―146 ± 54164 ± 10―168 ± 23
    AUC (μg∣min/ml)2386 ± 1293549 ± 4747682 ± 1054b1624 ± 171a2090 ± 265a4129 ± 568a,b

    • ↵a P < 0.05 compared with controls.

    • ↵b P < 0.05 compared with its antipode.

    • The em dashes indicate no value because of unidirectional chiral inversion of IB.

  • TABLE 4

    Compartmental pharmacokinetic parameters of each enantiomer after intravenous administration of R-IB or S-IB

    Results are expressed as the mean ± S.D. (n = 3).

    ParameterControlAA
    R-IBS-IBR-IBS-IB
    V1 (ml/kg)90.1 ± 20.067.2 ± 9.8113 ± 3899.3 ± 18.3
    V2 (ml/kg)78.5 ± 29.293.4 ± 72.2125 ± 52112 ± 69
    CLtot (ml/min/kg)4.28 ± 0.191.26 ± 0.12b6.87 ± 1.05a2.83 ± 0.92a, b
    CLRS (ml/min/kg)2.21 ± 0.53―3.81 ± 0.42a―
    CLMET (ml/min/kg)2.07 ± 0.321.26 ± 0.12b3.05 ± 0.42a2.83 ± 0.92a
    k0(R) (min−1)0.023 ± 0.003―0.029 ± 0.009―
    k12 (min−1)0.026 ± 0.0180.056 ± 0.0300.029 ± 0.0100.058 ± 0.020
    k21 (min−1)0.031 ± 0.0180.046 ± 0.0200.033 ± 0.0130.050 ± 0.017
    k10 (min−1)0.048 ± 0.0080.019 ± 0.004b0.060 ± 0.0080.028 ± 0.006b
    kRS (min−1)0.026 ± 0.011―0.032 ± 0.003―

    • ↵a P < 0.05 compared with controls.

    • ↵b P < 0.05 compared with its antipode.

    • The em dashes indicate no value because of unidirectional chiral inversion of IB.

  • TABLE 5

    Fi and T1/2inv of inversion calculated by AUC analysis, deconvolution method, and model analysis in control and AA rats

    Results are expressed as the mean ± S.D. (n = 3).

    ControlAA
    AUC analysis (FiAUC)aDeconvolution method (FiDECON)bModel analysis (FiCOMP)cAUC analysis (FiAUC)aDeconvolution method (FiDECON)bModel analysis (FiCOMP)c
    Fi0.47 ± 0.070.51 ± 0.130.52 ± 0.120.51 ± 0.080.53 ± 0.180.56 ± 0.05
    T1/2inv (min)―15.9 ± 4.429.7 ± 10.5―14.1 ± 3.425.8 ± 7.7

    • ↵a FiAUC = AUCR→S/AUCS→S.

    • ↵b Calculated using the deconvolution method.

    • ↵c FiCOMP = kRS/k0(R) + kRS.

    • The em dashes indicate no value because of unidirectional chiral inversion of IB.

  • TABLE 6

    Glucuronidation activities for R-IB and S-IB and P450 contents in control and AA rats

    Results are expressed as the mean ± S.D. (n = 3).

    ControlAA
    Glucuronidation activity (nmol/min/mg protein)R-IB0.23 ± 0.030.10 ± 0.01a
    S-IB0.71 ± 0.07b0.40 ± 0.04a,b
    P450 contents (nmol/mg protein)0.69 ± 0.100.48 ± 0.05a

    • ↵a P < 0.05 compared with controls.

    • ↵b P < 0.05 compared with its antipode.

  • TABLE 7

    Plasma levels of total protein and albumin in control and AA rats

    Results are expressed as the mean ± S.D. (n = 3).

    ControlAA
    Total protein (g/dl)6.9 ± 0.15.8 ± 0.1a
    Albumin (g/dl)2.7 ± 0.11.8 ± 0.1a

    • ↵a P < 0.05 compared with controls.

  • TABLE 8

    In vitro and in vivo plasma unbound fractions (fu) (%) of IB in control and AA rats

    Results are expressed as the mean ± S.D. (n = 3).

    ControlAA
    R-IBS-IBR-IBS-IB
    In vitro0.72 ± 0.241.38 ± 0.342.51 ± 0.56b,c3.40 ± 0.57b,c
    In vivoPost dosing (min)
    102.21 ± 0.322.96 ± 0.605.64 ± 0.66b,c8.38 ± 3.18b,c
    302.16 ± 0.293.59 ± 0.535.81 ± 0.77b,c7.42 ± 1.17b,c
    Averagea2.193.275.737.90

    • In vitro, Rac-IB (at a total concentration of 50 μg/ml); in vivo, dose, rac-IB 20 mg/kg. a) Average values between 10 and 30.

    • ↵b P < 0.05 compared with controls.

    • ↵c P < 0.05 compared with its antipode.

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Stereoselective Pharmacokinetics of Ibuprofen in Inflammation

Hiroyuki Ikuta, Atsushi Kawase and Masahiro Iwaki
Drug Metabolism and Disposition March 1, 2017, 45 (3) 316-324; DOI: https://doi.org/10.1124/dmd.116.073239
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