Table 3.
Drug‐specific parameters of the PBPK model
| Acetaminophen | Atenolol | Methotrexate | Morphine | Paliperidone | Phenytoin | Quinidine | Raclopride | Remoxipride | Risperidone | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Drug specific parameters | ||||||||||||
| Transmembrane permeability | cm/min | 1.1*10^‐4 | 5.7*10^‐5 | 6.1*10^‐7 | 2.5*10^‐4 | 0.0018 | 0.0077 | 0.058 | 6.6*10^‐4 | 0.0035 | 0.0082 | |
| Aqueous diffusivity coefficient (paracellular diffusion) | cm2/min | 4.6*10^‐4 | 3.5*10^‐4 | 2.8*10^‐4 | 3.4*10^‐4 | 2.8*10^‐4 | 3.6*10^‐4 | 3.2*10^‐4 | 3.1*10^‐4 | 3.0*10^‐4 | 2.9*10^‐4 | |
| AF | AFin1 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.2 | 1.0 | 1.0 | 1.0 | |
| AFin2 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.4 | 1.0 | 1.0 | 1.0 | ||
| AFin3 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.4 | 1.0 | 1.0 | 1.0 | ||
| AFout1 | 12 | 40 | 4.6*10^4 | 11a, 20b | 3.0 | 4.2 | 1.0 | 1.4 | 1.7 | 1.3 | ||
| AFout2 | 29 | 82 | 4.7*10^5 | 20a, 38b | 3.7 | 7.6 | 1.0 | 1.1 | 1.7 | 1.3 | ||
| AFout3 | 32 | 110 | 1.0*10^6 | 26a, 49b | 4.7 | 7.7 | 1.0 | 1.9 | 2.1 | 1.5 | ||
| Partitioning coefficient between compartments | ||||||||||||
| Kp,uu,brainECF | 0.51 | 0.37 | 0.018 | 0.38a, 0.23b | 0.50 | 0.26 | 1.5 | 1.1 | 0.80 | 0.97 | ||
| Kp,uu,CSFLV | 0.51 | 0.37 | 0.0066 | 0.38a, 0.23b | 0.50 | 0.26 | 1.5 | 1.1 | 0.80 | 0.97 | ||
| Kp,uu,CSFCM | 0.51 | 0.37 | 0.0024 | 0.38a, 0.23b | 0.50 | 0.26 | 1.5 | 1.1 | 0.80 | 0.97 | ||
| Kp | 1.0 | 0.94 | NA | 1.3 | 1.3 | 2.3 | 13 | 11 | 5.5 | 2.1 | ||
| Free fraction | ||||||||||||
| fu,p | 0.81 | 0.91 | 0.45 | 0.83 | 0.080 | 0.090 | 0.14 | 0.070 | 0.74 | 0.070 | ||
| fu,b | 0.80 | 0.90 | NA | 0.76 | 0.065d | 0.080 | 0.090 | 0.13 | 0.57c | 0.065 | ||
| Physicochemical properties | ||||||||||||
| Molecular weight | 151 | 266 | 454 | 285 | 426 | 252 | 324 | 347 | 371 | 410 | ||
| log P | 0.5 | 0.2 | −1.9 | 0.9 | 1.8 | 2.5 | 3.4 | 1.3 | 2.1 | 2.5 | ||
| pKa (acid) | 9.5 | 14.1 | 3.4 | 10.3 | 13.7 | 9.5 | 13.9 | 5.9 | 13.1 | |||
| pKa (base) | −4.4 | 9.7 | 2.8 | 9.1 | 8.8 | −9.0 | 9.1 | 9.0 | 8.4 | 8.8 | ||
| Charge class | Neutral | Base | Acid | Base | Base | Neutral | Base | Zwitterion | Base | Base | ||
AF, asymmetry factor; Kp,uu,brainECF, unbound brain extracellular fluid‐to‐plasma concentration ratio; Kp,uu,CSFLV, unbound CSFLV‐to‐plasma concentration ratio; Kp,uu,CSFCM, unbound CSFCM‐to‐plasma concentration ratio; Kp, total brain‐to‐plasma concentration ratio; fu,p, free fraction in plasma; fu,b, free fraction in brain.
AFin1–3 and AFout1–3 were calculated from Kp,uu,brainECF, Kp,uu,CSFLV, and Kp,uu,CSFCM, respectively.
a
4 mg/kg.
b
10, 40 mg/kg.
c
Calculated from Vu,brain, and Kp,uu,cell.
d
Assumed to be the same as risperidone.