Ca²⁺-mediated enhancement of anesthetic diffusion across phospholipid multilamellar systems

Although sharing common properties with other divalent cations, calcium ions induce fine-tuned electrostatic effects essential in many biological processes. Not only related with protein structure or ion channels, calcium is also determinant for other biomolecules such as lipids or even drugs. Cellular membranes are the first interaction barriers for drugs. Depending on their hydrophilic, hydrophobic or amphipathic properties, they have to overcome such barriers to permeate and diffuse through inner lipid bilayers, cells or even tissues. In this context, the role of calcium in the permeation of cationic amphiphilic drugs (CADs) through lipid membranes is not well understood. We combine differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR) to investigate the effect of Ca²⁺ on the interlamellar diffusion kinetics of the local anesthetic tetracaine (TTC) in multilamellar artificial membrane systems. Our DSC results show the interesting phenomenon that TTC diffusion can be modified in two different ways in the presence of Ca²⁺. Furthermore, TTC diffusion exhibits a thermal-dependent membrane interaction in the presence of Ca²⁺. The FTIR results suggest the presence of ion-dipole interactions between Ca²⁺ and the carbonyl group of TTC, leading us to hypothesize that Ca²⁺ destabilizes the hydration shell of TTC, which in turn diffuses deeper into the multilamellar lipid structures. Our results demonstrate the relevance of the Ca²⁺ ion in the drug permeation and diffusion through lipid bilayers.