Article Figures & Data
Figures
- Fig. 1.
Pharmacokinetic model for methylprednisolone with dose input either as an intramuscular injection (IM) or a subcutaneous infusion (SC); the symbols are defined in the text and Table 1. The model is described by eqs. 1 and 2.
- Fig. 2.
Schematic representation of diverse molecular and cellular mechanisms of corticosteroid action on regulating gene expression. CBG, corticosteroid-binding globulin; FKBP, FK506 binding protein; hsp 70/90, heat shock protein 70/90; nGRE, negative glucocorticoid response element; RNAP, RNA polymerase.
- Fig. 3.
PK/PD model schematic for the pharmacogenomic effects of corticosteroids and circadian rhythms on the transcriptional regulation of GILZ mRNA expression. Curved input represents circadian pattern in production, open boxes reflect stimulation, and solid boxes depict inhibition of production rate of a turnover process. The model is described by eqs. 3–12. Parameters are defined in Tables 2 and 3.
- Fig. 4.
MPL pharmacokinetics in rats. Simulated plasma concentrations versus time after 50 mg/kg intramuscular (IM) injection of MPL using eqs. 1 and 2. Pharmacokinetics of MPL upon administration of 0.3-mg/kg/h subcutaneous (SC) infusion for 7 days. Solid lines represent model fittings, circles depict the mean, and error bars depict 1 standard deviation (n = 3).
- Fig. 5.
Circadian rhythm of GR mRNA expression in three tissues from baseline-control animals. Circles represent the mean and error bars, 1 standard deviation (n = 3). The solid line depicts the fitting results using the PK/PD model depicted in Fig. 3. Unshaded regions depict the light phase and shaded regions, dark phase of the 24-hour cycle.
- Fig. 6.
GR mRNA expression in three tissues from rats given 50 mg/kg IM MPL. Circles represent the mean and error bars, 1 standard deviation (n = 3). The solid line depicts the fitting using the PK/PD model depicted in Fig. 3 and parameter estimates listed in Table 2.
- Fig. 7.
Circadian rhythm of GILZ mRNA expression in three tissues from baseline-control animals. Circles represent the mean and error bars, 1 standard deviation (n = 3). The solid line depicts the fitting results using the PK/PD model depicted in Fig. 3. The dashed line represents plasma corticosterone measurements from the same animals.
- Fig. 8.
GILZ mRNA expression in three tissues from rats given 50 mg/kg IM MPL. Circles represent the mean and error bars, 1 standard deviation (n = 3) The solid lines show model fittings (Fig. 3) using parameter estimates listed in Table 3.
- Fig. 9.
GILZ mRNA expression in lung and adipose tissue from rats infused with 0.3 mg/kg/h SC MPL for 7 days. Solid circles represent experimental data from individual rats, and solid lines are simulations using the PK/PD model depicted in Fig. 3. The parameters used are those for acute steroid effects listed in Table 3.
- Fig. 10.
Simulated profiles of the driving forces (GR mRNA, free cytosolic receptor, and drug-receptor complex in the cytosol and nucleus) controlling GILZ regulation in lung and adipose tissue from rats infused with 0.3 mg/kg/h MPL for 7 days. Simulations are based on the model in Fig. 3. The parameters are those for acute MPL effects as listed in Tables 2 and 3.
Tables
Parameter Definition Estimate (CV%) F Bioavailability 0.214a,b/1.0c Fr Fraction absorbed by ka1 0.73a,b/NAc ka1 (h−1) Absorption rate constant 1.26a,b/NAc ka2 (h−1) Absorption rate constant 0.22a,b/NAc VP (ml/kg) Plasma volume of distribution 718.7a,b,c VT (ml/kg) Tissue volume of distribution 913.5a,b,c CLD (l/h/kg) Distribution clearance 2.6a,b,c CL (l/h/kg) Clearance 4.0a,b/8.3c (10.1) Parameter Definition Estimate (CV%) a0,GRm Fourier coefficient for GR mRNA 2824a/1055.9b/2216c,d a1,GRm Fourier coefficient for GR mRNA 6.8a/162.2b/−273.2c,d a2,GRm Fourier coefficient for GR mRNA 65.9c,d b1,GRm Fourier coefficient for GR mRNA 185.6a/−19.9b/−10.9c,d b2,GRm Fourier coefficient for GR mRNA 10.1c,d kd,GRm (h−1) Degradation rate constant for GR mRNA 0.26 (15.4)a/0.28b (29.9)/0.31c,d ks,GR (nM/h)(mol/ng)-1 Synthesis rate constant for receptor 0.00025 (5.3)a/0.00121b (34.5)/0.00196c,d IC50,GRm (nM−1) Inhibition of GR mRNA production 15.6e kd,GR (h−1) Degradation rate constant for receptor 0.05e kon (nM−1·h−1) Association rate constant 0.016e fmpl Unbound fraction of MPL in plasma 0.23e kre (h−1) DRn loss rate constant 1.31e Rf Fraction recycled 0.93e kT (h−1) Translocation rate constant 58.3e GRm,MPL (0) (mol/ng RNA) GR mRNA initial concentration (treatment) 4000 (fixed)a/1350b (10.7)/2200c,d GR(0) (nM) Free cytosolic receptor initial concentration 19.7 (5.3)a/32.7b (34.5)/86.2c,d DR(0) (nM) Drug-receptor complex initial concentration 0 (fixed) DRn(0) (nM) Nuclear complex initial concentration 0 (fixed) Parameter Definition Estimate (CV%) a0,GILZm Fourier coefficient for GILZ mRNA 14,002a/6479b/9845c a1,GILZm Fourier coefficient for GILZ mRNA −3447a/1133b/-441c b1,GILZm Fourier coefficient for GILZ mRNA −8339a/-1651b/−5148c kd,GILZm (h−1) Degradation rate constant for GILZ mRNA 0.45a (7.7)/0.16b (14.3)/0.21c (5.8) SDRnGILZm (nM−1) Stimulation of GILZ mRNA production 0.47a (6.8)/0.27b (40.0)/0.3c (8.3) GILZmMPL (0) (mol/ng RNA) GILZ mRNA initial concentration (treatment) 10,560a (fixed)/4249b (17.9)/6077c (21.3)
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Modeling Tissue-Specific Pharmacogenomics of Steroid Action
