Overall unbound cytoplasmic/perfusate distribution ratio and ratios for intracellular, lysosomes, and mitochondria to perfusate concentrations for model cationic drugs
| Drug | pKa4-a | Intracellular to Perfusate Concentration Ratio (i:p)4-b | Lysosomes to Perfusate Concentration Ratio (l:p)4-c | Mitochondria to Perfusate Concentration Ratio (m:p)4-d | Overall Unbound Cytoplasmic/Perfusate Distribution Ratio (c:p)4-e | Predictedkin/kout4-f | Experimentalkin/kout4-g |
|---|---|---|---|---|---|---|---|
| Atenolol | 9.60 | 1.35 | 498.05 | 5.34 | 7.11 | 12.23 | 8.00 ± 1.75 |
| Antipyrine | 1.45 | 1.00 | 1.00 | 1.00 | 1.00 | 1.72 | 1.72 ± 0.73 |
| Prazosin | 6.50 | 1.04 | 56.93 | 1.49 | 1.69 | 2.91 | 3.37 ± 1.13 |
| Labetalol | 7.40 | 1.17 | 251.09 | 3.19 | 4.08 | 7.02 | 6.10 ± 1.07 |
| Propranolol | 9.45 | 1.35 | 496.77 | 5.33 | 7.10 | 12.21 | 9.76 ± 2.60 |
| Diltiazem | 7.70 | 1.23 | 334.19 | 3.91 | 5.10 | 8.77 | 7.35 ± 1.25 |
↵4-a From Table 1.
↵4-b Intracellular to perfusate concentration ratio = (1 + 10p Ka −pHi)/(1 + 10p Ka −pHp) (Goldstein et al., 1974), where pHi = 7.27 is the intracellular pH (Le Couteur et al., 1993) and pHp = 7.40 is the perfusate pH.
c,d Using the same equation as footnote b.
↵4-c Where pHi = 4.70 is the lysosomes pH (Myers et al., 1995; Proost et al., 1997).
↵4-d Where pHi = 6.67 is the mitochondria pH in the fasted state (Soboll et al., 1980).
↵4-e Given that the fraction of lysosomes (f lys) and mitochondria (f mito) to cytosol is 1 and 20% (Rhoades and Pflanzer, 1996), the cytoplasmic/plasma distribution ratio (c:p) for model cationic drugs can be estimated from the individual organelle and remaining cytoplasmic volume fractions and concentration ratios above using the equation: c:p = [f lys× l:p + f mito × m:p + (1 −f lys − f mito) × i:p].
↵4-f Predictedk in/k out is given by c:p multiplied by 1.72, the k in/k outfor antipyrine (Table 3), which is a cationic drug essentially un-ionized at pH values 4.7 to 7.4.
↵4-g Ratios ofk in/k out from Table 3.