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Research ArticleArticle

Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors

Joana Bicker, Ana Fortuna, Gilberto Alves, Patrício Soares-da-Silva and Amílcar Falcão
Drug Metabolism and Disposition December 2017, 45 (12) 1282-1291; DOI: https://doi.org/10.1124/dmd.117.077883
Joana Bicker
Laboratory of Pharmacology, Faculty of Pharmacy (J.B., A.Fo., A.Fa.), and Center for Neuroscience and Cell Biology (J.B., A.Fo., G.A., A.Fa.), University of Coimbra, Coimbra, Portugal; Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal (G.A.); Department of Research and Development, BIAL, Sao Mamede do Coronado, Portugal (P.S.-d.S.); and Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal (P.S.-d.S.)
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Ana Fortuna
Laboratory of Pharmacology, Faculty of Pharmacy (J.B., A.Fo., A.Fa.), and Center for Neuroscience and Cell Biology (J.B., A.Fo., G.A., A.Fa.), University of Coimbra, Coimbra, Portugal; Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal (G.A.); Department of Research and Development, BIAL, Sao Mamede do Coronado, Portugal (P.S.-d.S.); and Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal (P.S.-d.S.)
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Gilberto Alves
Laboratory of Pharmacology, Faculty of Pharmacy (J.B., A.Fo., A.Fa.), and Center for Neuroscience and Cell Biology (J.B., A.Fo., G.A., A.Fa.), University of Coimbra, Coimbra, Portugal; Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal (G.A.); Department of Research and Development, BIAL, Sao Mamede do Coronado, Portugal (P.S.-d.S.); and Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal (P.S.-d.S.)
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Patrício Soares-da-Silva
Laboratory of Pharmacology, Faculty of Pharmacy (J.B., A.Fo., A.Fa.), and Center for Neuroscience and Cell Biology (J.B., A.Fo., G.A., A.Fa.), University of Coimbra, Coimbra, Portugal; Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal (G.A.); Department of Research and Development, BIAL, Sao Mamede do Coronado, Portugal (P.S.-d.S.); and Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal (P.S.-d.S.)
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Amílcar Falcão
Laboratory of Pharmacology, Faculty of Pharmacy (J.B., A.Fo., A.Fa.), and Center for Neuroscience and Cell Biology (J.B., A.Fo., G.A., A.Fa.), University of Coimbra, Coimbra, Portugal; Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal (G.A.); Department of Research and Development, BIAL, Sao Mamede do Coronado, Portugal (P.S.-d.S.); and Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal (P.S.-d.S.)
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  • Fig. 1.
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    Fig. 1.

    Chemical structures of the analyzed COMT inhibitors.

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    Fig. 2.

    Intracellular accumulation of rhodamine-123 and Hoechst 33342 in MDCK II, MDCK-MDR1, and MDCK-BCRP cells. (A and B) Demonstration of P-gp and BCRP functionality after a 30-minute incubation period with 100 µM verapamil (A) or 0.5 µM Ko143 (B) as positive controls. (C and D) Intracellular uptake observed following a 30-minute incubation period with 100 µM test compounds in MDCK-MDR1 (C) and MDCK-BCRP (D) cells. Data compared with negative control cells (no inhibitor) and expressed as mean ± S.D. (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001.

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    Fig. 3.

    Dose-dependent inhibition of BCRP-mediated accumulation of Hoechst 33342 by BIA 9-1079 (A), nebicapone (B), and tolcapone (C) in MDCK-BCRP cells. Values represent mean ± S.D. (n = 3).

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    Fig. 4.

    Mean concentration-time profiles of BIA 9-1079 and tolcapone in plasma (A) and brain (B) following 10 mg/kg intravenous administration to Wistar rats. Each data point is presented as mean ± S.E.M. (n = 27–30 animals per group). The mean concentration-time profiles of BIA 9-1079 and tolcapone in plasma (C and E) and brain (D and F) with and without the coadministration of elacridar (2.5 mg/kg) are depicted. Each data point is presented as mean ± S.E.M. (n = 8–12 animals per group) and significant differences between group concentrations at specific time points were calculated by two-tailed Student’s t test. *P < 0.05; **P < 0.01.

Tables

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    TABLE 1

    Bidirectional Papp coefficient, ER, and net flux ratio of reference compounds across MDCK II, MDCK-MDR1, and MDCK-BCRP cell monolayers

    The Papp values are indicated from the AP-BL and BL-AP compartments and are expressed as mean (S.D.) (n = 3). ERs and net flux ratios greater than 2 are marked in bold. Transport classification according to Mahar Doan et al. (2002), Pavek et al. (2005), Wang et al. (2005), Feng et al. (2008), and Urquhart et al. (2008).

    Reference CompoundTransportDonor SolutionMDCK IIMDCK-MDR1Net Flux RatioMDCK-BCRPNet Flux Ratio
    Papp,AP-BL (×10−6)Papp,BL-AP (×10−6)ERPapp,AP-BL (×10−6)Papp,BL-AP (×10−6)ERWithout VerapamilWith VerapamilPapp,AP-BL (×10−6)Papp,BL-AP (×10−6)ERWithout Ko143With Ko143
    μMcm/scm/scm/scm/scm/scm/s
    CarbamazepinePT1036.5 (1.93)19.5 (0.60)0.5338.0 (2.54)20.0 (5.53)0.531.00—37.3 (5.60)19.6 (3.85)0.531.00—
    PropranololPT1019.6 (4.99)20.0 (0.16)1.0223.8 (2.69)20.8 (1.51)0.870.85—25.4 (2.51)22.4 (0.59)0.880.86—
    TrazodonePT1038.5 (3.30)29.4 (1.31)0.7633.0 (2.58)40.4 (3.14)1.221.61—37.5 (5.03)27.4 (2.91)0.730.96—
    AtenololPP1000.22 (0.06)0.28 (0.03)1.270.35 (0.14)0.24 (0.04)0.690.54—0.14 (0.11)0.20 (0.03)1.431.13—
    CimetidineEffluxa300.56 (0.14)0.43 (0.03)0.750.06 (0.02)0.41 (0.05)6.408.500.890.15 (0.04)1.25 (0.08)8.3411.11.47
    QuinidineEffluxb109.52 (2.53)12.5 (2.49)1.313.77 (0.91)29.1 (1.37)7.735.901.1312.0 (3.48)15.0 (0.48)1.250.95—
    SulfasalazineEffluxc600.81 (0.30)0.28 (0.05)0.340.30 (0.14)0.17 (0.09)0.561.64—0.13 (0.11)0.30 (0.05)2.316.790.92
    Na-FPP1000.48 (0.09)——0.09 (0.08)————0.11 (0.04)————
    • PP, passive paracellular; PT, passive transcellular.

    • ↵a Efflux mediated by P-gp and BCRP.

    • ↵b Efflux mediated by P-gp.

    • ↵c Efflux mediated by BCRP.

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    TABLE 2

    The Papp coefficient values, ER, and net flux ratio of COMT inhibitors across MDCK II, MDCK-MDR1, and MDCK-BCRP cell monolayers

    The Papp values are indicated from the AP-BL and BL-AP compartments and are expressed as mean (S.D.) (n = 3). ERs and net flux ratios greater than 2 are marked in bold.

    Test CompoundDonor SolutionMDCK IIMDCK-MDR1Net Flux RatioMDCK-BCRPNet Flux Ratio
    Papp,AP-BL (×10−6)Papp,BL-AP (×10−6)ERPapp,AP-BL (×10−6)Papp,BL-AP (×10−6)ERWithout VerapamilWith VerapamilPapp,AP-BL (×10−6)Papp,BL-AP (×10−6)ERWithout Ko143With Ko143
    μMcm/scm/scm/scm/scm/scm/s
    BIA 9-1059601.29 (0.27)1.47 (0.18)1.141.22 (0.23)0.35 (0.07)0.290.25—0.24 (0.08)1.69 (0.44)7.046.180.64
    BIA 9-1079105.23 (2.75)8.47 (0.91)1.623.47 (1.77)15.9 (4.19)4.582.830.607.14 (4.63)13.6 (1.74)1.901.17—
    Entacapone306.33 (0.37)6.02 (0.39)0.953.51 (1.33)1.29 (0.36)0.370.39—0.98 (0.19)11.1 (0.92)11.311.91.06
    Nebicapone1024.6 (1.45)17.6 (4.18)0.7223.9 (7.06)14.3 (2.60)0.600.83—5.40 (0.09)11.6 (0.63)2.152.991.07
    Opicapone304.72 (2.33)6.08 (0.38)1.292.56 (1.08)2.50 (0.39)0.980.76—0.42 (0.09)9.73 (1.13)23.218.01.58
    Tolcapone1026.6 (5.07)20.6 (3.87)0.7724.3 (2.84)19.5 (3.37)0.801.04—28.3 (2.93)23.7 (1.65)0.841.09—
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    TABLE 3

    Pharmacokinetic parameters of BIA 9-1079 and tolcapone in plasma and brain after intravenous administration (10 mg/kg) to Wistar rats

    The Cmax values are expressed in micrograms/gram and the AUC is expressed in micrograms.hour/gram in brain tissue.

    Test CompoundtmaxCmaxAUC0-tAUC0-infAUCextrapKelt1/2elMRT
    hμg/mlμg.h/mlμg.h/ml%/hhh
    BIA 9-1079
     Plasma0.0352.7884.0884.941.020.135.392.46
     Brain0.080.0960.017NCNC0.661.050.23
    Tolcapone
     Plasma0.0367.1236.2436.280.100.511.361.09
     Brain0.030.2050.0560.0571.791.530.450.38
    • AUCextrap, extrapolated area under the concentration-time curve; AUC0-inf, area under the concentration-time curve from time zero to infinite; AUC0-t, area under the concentration-time curve from time zero to the last measurable concentration; Kel, apparent elimination rate constant; MRT, mean residence time; NC, not calculated; t1/2el, apparent terminal elimination half-life; tmax, time to achieve the maximum concentration.

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    TABLE 4

    Pharmacokinetic parameters and binding data of BIA 9-1079 and tolcapone in plasma and brain after intravenous administration (10 mg/kg) to Wistar rats

    The presented Vu,bram,pred, Kp,uu,cyto,pred, Kp,uu,lyso,pred, and Kp,uu,ceii,pred values were predicted according to the pH partitioning theory. The fu,plasma and fu,brain values are expressed as mean (S.D.), n = 4.

    Test CompoundKpfu,plasmafu,brainfu,brain,correctedVu,brain,predKp,uuKp,uu,cyto,predKp,uu,lyso,predKp,uu,cell,pred
    ml/g
    BIA 9-10790.00020.002 (0.001)0.008 (0.001)0.01379.270.0010.5770.0200.656
    Tolcapone0.00150.011 (0.003)0.162 (0.028)0.2474.0470.0350.5750.0130.655
    • fu,plasma, unbound drug fraction in plasma; Kp, ratio of total brain-to-plasma AUC0-t; Kp,uu, unbound brain-to-plasma ratio; Kp,uu,cell,pred, predicted unbound drug intracellular-to-extracellular partitioning coefficient; Kp,uu,cyto,pred, predicted unbound cytosolic-to-extracellular drug concentration ratio; Kp,uu,lyso,pred, predicted lysosomic-to-cytosolic unbound drug concentration ratio; Vu,brain,pred, predicted volume of distribution of unbound drug in the brain.

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    TABLE 5

    Plasma and brain exposure of BIA 9-1079 and tolcapone after intravenous administration (10 mg/kg) to Wistar rats with or without coadministration of elacridar (2.5 mg/kg)

    The AUC is expressed in micrograms.hour/gram in brain tissue.

    Test CompoundAUC0-tKpKp,uu
    VehicleElacridarVehicleElacridarVehicleElacridar
    μg.h/mlμg.h/ml
    BIA 9-1079
     Plasma32.7137.340.0010.0030.0070.017
     Brain0.0370.095
    Tolcapone
     Plasma27.3128.590.0020.0040.0410.095
     Brain0.0500.119
    • AUC0-t, area under the concentration-time curve from time zero to the last measurable concentration; Kp, ratio of total brain-to-plasma AUC0-t; Kp,uu, unbound brain-to-plasma ratio.

Additional Files

  • Figures
  • Tables
  • Data Supplement

    • Supplemental Tables -

      Supplemental Table 1 - Chromatographic conditions and validation parameters of HPLC-DAD techniques applied for the quantification of reference and test compounds in samples from in vitro and in vivo assays

      Supplemental Table 2 - Stability (values in percentage) of COMT inhibitors in HBSS with 10mM HEPES pH 7.4 under cellular assay conditions (37º C for 120 min)

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Drug Metabolism and Disposition: 45 (12)
Drug Metabolism and Disposition
Vol. 45, Issue 12
1 Dec 2017
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Research ArticleArticle

P-gp and BCRP Impact on the Brain Access of COMT Inhibitors

Joana Bicker, Ana Fortuna, Gilberto Alves, Patrício Soares-da-Silva and Amílcar Falcão
Drug Metabolism and Disposition December 1, 2017, 45 (12) 1282-1291; DOI: https://doi.org/10.1124/dmd.117.077883

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Research ArticleArticle

P-gp and BCRP Impact on the Brain Access of COMT Inhibitors

Joana Bicker, Ana Fortuna, Gilberto Alves, Patrício Soares-da-Silva and Amílcar Falcão
Drug Metabolism and Disposition December 1, 2017, 45 (12) 1282-1291; DOI: https://doi.org/10.1124/dmd.117.077883
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