Bilayer-modifying potency of antipsychotics as a function of pH.

Abstract

Antipsychotic drugs (APDs) have complex pharmacological profiles with a range of putative membrane protein targets and off-target effects. We have previously shown that APDs, including chlorpromazine (CPZ) and trifluoperazine (TFP), alter lipid bilayer properties as detected by bilayer-spanning gramicidin channels, which raises the possibility that at least part of their non-specific effects may be mediated by the bilayer. Following Malheiros et al. (1998) and Ahyayaych et al. (2003), who showed that the bilayer affinity of a titratable drug depends on its charge, being higher for neutral molecules, we explored the role of charge on the bilayer-modifying potencies of CPZ and TFP at pHs between 4 and 10. (Short-term exposure to pH 10 does not cause measurable changes in bilayer properties.) Using dynamic and electrophoretic light scattering to monitor partitioning of the charged species, we found that increasing pH produced a decrease in the magnitude of the zeta potential for both CPZ and TFP with little effect on the particle size distribution. Using gramicidin channels as probes, we found that the bilayer-modifying potencies of the drugs varied with changes in pH: the potency of CPZ increased modestly with increasing pH, while the potency of TFP varied little at low concentrations (3 and 10 µM) but decreased as pH increased at 30 µM. From experiments changing the total lipid concentration in the system, we found that the apparent partition coefficient of CPZ increased from pH 4 to pH 10, whereas that for TFP decreased. We conclude that the bilayer-modifying potency of a titratable drug is different for the neutral and charged species, with the charged species being more bilayer-modifying per molecule in the membrane.