Table 2.
Concentrations for half-maximal tonic and use-dependent block of sodium currents by Mex and its metabolites
| Compound | Tonic block IC50 (μM) | Ratio | Use-dependent block 10 Hz IC50 (μM) | Ratio | TB/UDB |
|---|---|---|---|---|---|
| Mex | 75.3±8.0 | 1 | 23.6±2.8 | 1 | 3.2 |
| PHM | 309.1±8.5 | 4 | 84.8±8.3 | 3.6 | 3.1 |
| HMM | 412.1±45.5a | 5.5 | 65.1±4.2 | 2.8 | 6.3 |
| NHM | 663.0±67.8a,b | 9 | 241.9±14.1a,b | 10 | 2.7 |
| NMG | >1000 | >10 | >500 | >20 | ∼2 |
Abbreviations: HMM, hydroxy-methyl-mexiletine; IC50, half-maximal blocking concentration; Mex, mexiletine; NHM, N-hydroxy-mexiletine; NMG, N-carbonyloxy β-D-glucuronide; PHM, p-hydroxy-mexiletine.
Concentrations able to produce half-maximal response (IC50, μM) in producing a tonic block and a use-dependent block. The ratio between IC50 values during tonic and use-dependent block (IC50 TB/IC50 UDB 10 Hz) is shown in order to allow a more easy comparison of the use-dependent behaviour of each compound. The IC50 values have been obtained during non-linear least-squares fit of the concentration–response data to the logistic equation described in Methods. The ratio between IC50 value of each compound and IC50 value of Mex, for the tonic and use-dependent block, is also shown to better evaluate the relative potency towards parent compound.
The IC50 values of each metabolite for tonic and use-dependent block were significantly different with respect to those of Mex (P<0.001).
a and b show the statistic significance by Student's t-test between the metabolites (for P<0.01 or less) as follows:
With respect to PHM.
With respect to HMM.