Chemical properties of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine used for PBPK modeling

The acid dissociation constant (pKa), plasma unbound fraction (fu,p), and octanol-water partition coefficient (logP) values for atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine were obtained by in silico estimation using ACD/Percepta, Simcyp, and ChemDraw software, respectively. Parameters such as fu,p, Rb, and Kp,h are assumed to be the same in mice and humans.

Molecular weightMW255271241
Octanol-water partition coefficientlogP3.943.453.67
Acid dissociation constantpKa9.6 (base)9.4 (base)
10.4 (acid)
9.2 (base)
Plasma unbound fractionfu,p0.1570.7500.194
Blood-plasma concentration ratioRb0.8720.8270.889
Liver-plasma concentration ratioKp,h7.279.837.15
  • The liver (kidney)-to-plasma concentration ratios (Kp,h/Kp,r) and the blood-to-plasma concentration ratio (Rb) were calculated from the fu,p, and logP values as follows (Adachi et al., 2023c): Embedded Image Embedded Image Embedded Image