Neuronal safety of Kv11.1 blockers: Patch-clamp and in vitro evaluation with physiologically based pharmacokinetic...

Class III antiarrhythmic drugs are indispensable for cardiac rhythm control, yet their susceptibility to clinically used ion channel modulating drugs remains insufficiently characterized. Because Kv11.1 channels are present in neurons and glia, their pharmacological engagement may influence excitability and cell viability. Here, we investigated Sotalol, Ibutilide, and Amiodarone, three clinically used Kv11.1 active compounds with distinct lipophilicity profiles, using an integrated strategy that combines whole-cell patch-clamp electrophysiology, cell viability assays, and physiologically based pharmacokinetic (PBPK) modeling in neuron-like SH-SY5Y cells, a human model widely used for neurotoxicity and ion-channel studies. Sotalol produced minimal electrophysiological changes, whereas Ibutilide caused moderate suppression of outward K⁺ currents, and Amiodarone did not show acute effects under our patch-clamp conditions. However, Amiodarone induced pronounced morphological changes and loss of viability in vitro, while Ibutilide showed moderate cytotoxicity and Sotalol caused minimal metabolic alterations. PBPK simulations contextualized these findings, predicting extensive, time-dependent brain accumulation of Amiodarone, moderate entry of Ibutilide, and minimal penetration of Sotalol. Together, these data reveal a clear link between drug lipophilicity, brain exposure, and neuronal vulnerability. Amiodarone's high lipid solubility drives persistent intracellular retention and cytotoxic morphology, while Ibutilide primarily exerts transient electrophysiological effects. This integrated PBPK-in-vitro framework provides a mechanistic basis for differentiating CNS risk among antiarrhythmics and highlights lipophilicity and broad ion channel activity as key determinants of neuronal safety.