Comparison of predicted and observed, model-derived Kv (equilibrium amount ratio characterizing the vesicular ion-trapping) values for the three model drugs
Drug | pKa | Lysosomal to Intracellular Concentration Ratioa | Mitochondrial to Intracellular Concentration Ratioa | Predicted Kvb | Observed Model-Derived Kvc |
|---|---|---|---|---|---|
| Atenolol | 9.60 | 738 | 3.97 | 8.17 | 7.37 ± 1.89 |
| Antipyrine | 1.45 | 1.00 | 1.00 | 0.21 | 0.24 ± 0.06 |
| Propranolol | 9.45 | 736 | 3.96 | 8.16 | 8.97 ± 1.79 |
↵ a Vesicular to cytosolic concentration ratio = (1 + 10pKa - pHv)/(1 + 10pKa - pHi) (Myers et al., 1995), where pHi ≈ 7.27 is the assumed cytosolic pH (Le Couteur et al., 1993), pHv ≈ 4.4 is the assumed lysosomal pH (Daniel et al., 2001) and pHv ≈ 6.67 is the assumed mitochondrial pH in the fasted state (Pietri et al., 2001)
↵ b Given that of lysosomal and mitochondrial to the cytosolic fraction is 1 and 20% (Rhoades and Pflanzer, 1996), the overall unbound drug vesicles/intracellular distribution ratio (v:i) for the three model drugs can be estimated from the individual organelle volume fraction and concentration ratio above using the equation: Kv = flys × l:i + fmito × m:i
↵ c Data fitting results using the physiological two-phase organ pharmacokinetic model