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Research ArticleNeuropharmacology

Pharmacokinetic-Pharmacodynamic Modeling of Brain Dopamine Levels Based on Dopamine Transporter Occupancy after Administration of Methylphenidate in Rats

Ryosuke Shimizu, Naotaka Horiguchi, Koji Yano, Masashi Sakuramoto, Naoki Kanegawa, Shunji Shinohara and Shuichi Ohnishi
Journal of Pharmacology and Experimental Therapeutics April 2019, 369 (1) 78-87; DOI: https://doi.org/10.1124/jpet.118.252262

Article Figures & Data

Figures

  • Fig. 1.
    Fig. 1.

    Scheme of the in vitro study. The experiment in the absence (a) or presence (b) of methylphenidate. To observe the uptake of the DAT substrate, which is composed of masking dye and fluorophore, the masking dye is removed and only the fluorophore is transported into the cell. Therefore, the transport activity of the DAT substrate was investigated by measuring the fluorescence captured from the intracellular fluorophore. To measure fluorescence, the fluorophore was excited with light at a wavelength of 470–495 nm, and emission was collected at 515–575 nm. Each parameter is defined as follows: Cinh, concentration of inhibitor; koff, dissociation rate constant of methylphenidate for DAT (per minute); k′on permeability rate constant for fluorescent substrate via DAT (per minute); kon, association rate constant of methylphenidate for DAT (micromolars per minute).

  • Fig. 2.
    Fig. 2.

    The structure of the PK-PD model for dopamine levels in the brain after intraperitoneal administration of methylphenidate. Each parameter is defined as follows: Central, central compartment; CSF, cerebrospinal flow compartment; DAT, DAT occupancy compartment; Ip, administration compartment; k12, first-order rate constant from the plasma to peripheral compartment; k21, first-order rate constant from the peripheral to plasma compartment; ka, absorption rate constant; kdeg, degradation rate constant of dopamine in the synapse; ke, elimination rate constant from the central compartment; krelease, first-order rate constant for dopamine release via DAT; ksyn, synthesis rate constant of dopamine in the synapse; kuptake, first-order rate constant for dopamine reuptake from the synapse; Periph, peripheral compartment.

  • Fig. 3.
    Fig. 3.

    The time course of observed and predicted fluorescent strength in the absence and presence of methylphenidate. The concentrations of methylphenidate were 0.0781–2.50 μM. Plots show observed data in the absence (diamonds) or presence (circles) of methylphenidate and lines show predicted data in the absence (solid lines) or presence (dashed lines) of methylphenidate.

  • Fig. 4.
    Fig. 4.

    The time course of observed and predicted fluorescent strength in the absence and presence of cocaine. The concentrations of cocaine were 0.313 and 0.625 μM. Plots show observed data in the absence (diamonds) or presence (circles) of cocaine and lines show predicted data in the absence (solid lines) or presence (dashed lines) of cocaine.

  • Fig. 5.
    Fig. 5.

    The time-course profiles of observed and predicted concentrations of methylphenidate in plasma after intraperitoneal administration in Wistar rats for pharmacokinetic study groups. Each symbol represents the observed mean ± S.D. (n = 3–5) at 1 mg/kg (open diamonds), 3 mg/kg (gray diamonds), and 6 mg/kg (black diamonds), and each line represents the predicted value at 1 mg/kg (solid lines), 3 mg/kg (gray lines), and 6 mg/kg (dashed lines). Normal scale (a) and semilog scale (b).

  • Fig. 6.
    Fig. 6.

    The time-course profiles of observed and predicted dopamine levels after single intraperitoneal administration of methylphenidate to Wistar rats for pharmacodynamics study groups. Each symbol represents the observed mean ± S.D. (n = 4) and each line represents the predicted value at 1 mg/kg (a), 3 mg/kg (b), and 6 mg/kg (c).

  • Fig. 7.
    Fig. 7.

    Calculated occupancy for dopamine transporter after intraperitoneal administration of methylphenidate at 1 mg/kg (solid line), 3 mg/kg (gray line), and 6 mg/kg (dashed line).

  • Fig. 8.
    Fig. 8.

    The relationship between dopamine transporter occupancy and dopamine reuptake calculated using the equation: dopamine reuptake = (1 − DATRO)γ. The dashed line shows the correlation in the case of γ = 1 and the solid line shows the correlation in the case of γ = 0.578 (our result).

Tables

  • TABLE 1

    Estimated in vitro kinetic parameters (CV%) for fluorescent substrate and methylphenidate

    Tested ConcentrationCsubk′onkonkoffKd
    μMminμM/minminμM
    Control2360 (0.32)0.0427 (0.99)———
    Methylphenidate
     0.0781——0.926 (1.72)0.0777 (1.94)0.084
     0.156——1.20 (1.73)0.0818 (2.23)0.079
     0.313——1.24 (3.66)0.129 (4.28)0.104
     0.625——2.31 (2.76)0.250 (2.90)0.108
     1.25——1.14 (2.53)0.146 (2.78)0.128
     2.50——0.810 (3.71)0.122 (4.19)0.151
    Cocaine
     0.313——0.492 (1.34)0.123 (1.64)0.250
     0.625——0.512 (1.55)0.134 (1.67)0.261

    • Kd, dissociation constant for methylphenidate or cocaine and calculated as koff/kon (micromolars); koff, dissociation rate constant of methylphenidate or cocaine for DAT (per minute); k′on, permeability rate constant for fluorescent substrate via DAT (per minute); kon, association rate constant of methylphenidate or cocaine for DAT (micromolars per minute).

    • —, not estimated.

  • TABLE 2

    Pharmacokinetic parameters of methylphenidate in plasma after single intraperitoneal administration of methylphenidate to rats

    Data represent mean ± S.D. (n = 3–5).

    DoseCmaxAUC0–infTmaxKp_brainKp_CSF
    mg/kgng/mlng·h/mlmin
    1139 ± 42.539.0 ± 7.962.0 ± 0.010.6 ± 0.851.31 ± 0.13
    3435 ± 84.2166 ± 0.7272.0 ± 0.011.2 ± 1.231.20 ± 0.04
    61030 ± 143372 ± 53.52.6 ± 1.311.2 ± 1.071.66 ± 0.19

    • Kp_brain, brain-to-plasma concentration ratio; Tmax, time to reach the maximum plasma concentration.

  • TABLE 3

    Pharmacodynamic parameters of methylphenidate in microdialysate after single intraperitoneal administration of methylphenidate to rats

    Data represent mean ± S.D. (n = 4).

    DoseLmax_ddAUEallTmax_d
    mg/kg(% of baseline)(% of baseline × min)min
    1260 ± 1327633 ± 838525.5 ± 22.7
    3346 ± 1109418 ± 321619.5 ± 13.3
    6455 ± 72.520,324 ± 441416.5 ± 7.55

    • dAUEall, change in the area under the effect-time curve for the dopamine level from time zero to the last time; Lmax_d, maximum dopamine level; Tmax_d, time to reach the maximum dopamine level.

  • TABLE 4

    Parameters of methylphenidate estimated by mechanism-based pharmacokinetic and pharmacodynamic model

    ParameterDefinitionEstimateCV
    %
    ka (min)Absorption rate constant7.778.18
    k12 (min)First-order rate constant from the plasma to peripheral compartment0.014138.5
    k21 (min)First-order rate constant from the peripheral to plasma compartment0.033027.2
    ke (min)Elimination rate constant from the central compartment0.05517.34
    Vd/F (l/kg)Distribution volume of methylphenidate in the central compartment5.598.03
    Kp_CSFCSF-to-plasma concentration ratio1.25Observed
    kdeg (min)Degradation rate constant of dopamine in the synapse0.0282121
    krelease (min)First-order rate constant for dopamine release via DAT0.062949.8
    kuptake (min)First-order rate constant for dopamine reuptake from the synapse0.53320.3
    γHill coefficient0.5788.18
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Research ArticleNeuropharmacology

Dopamine PK-PD Model of Methylphenidate

Ryosuke Shimizu, Naotaka Horiguchi, Koji Yano, Masashi Sakuramoto, Naoki Kanegawa, Shunji Shinohara and Shuichi Ohnishi
Journal of Pharmacology and Experimental Therapeutics April 1, 2019, 369 (1) 78-87; DOI: https://doi.org/10.1124/jpet.118.252262
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