Although non-ionic surfactants are common pharmaceutical excipients, their direct effects on voltage-gated sodium channels are not well understood. Here, we investigated the effects of polysorbate 80 (PS80) on Na v 1.7, a key determinant of nociceptor excitability, using whole-cell patch clamp electrophysiology in both rat dorsal root ganglion (DRG) neurons and HEK293 cells stably expressing the channel. Our results show that PS80 inhibits Na v 1.7 in a voltage-dependent manner, with inhibition enhanced at more depolarized potentials. PS80 induced a significant hyperpolarizing shift in the steady-state inactivation curve and slowed the recovery from inactivation, indicating a preferential stabilization of the inactivated channel state. To identify the structural motifs responsible for this inhibition, we compared the effects of PS80 with those of other non-ionic polyoxyethylene-based surfactants, including Triton X-100 and NP-40, as well as with PEG400. Collectively, our findings establish a structure-activity relationship for the unintended inhibition of Na v 1.7 by non-ionic surfactants. This provides a biophysical rationale for selecting appropriate excipients and has significant implications for drug safety, potential assay interference, and formulation strategies in drug development.
Kim et al. (Sun,) studied this question.