Thermodynamics and kinetics of joint action of antiviral agent tilorone and DMSO on model lipid membranes

Abstract

Individual and joint action of two water-soluble drugs, DMSO and tilorone, on model l-α-dipalmitoylphosphatidylcholine (DPPC) membranes were studied in equilibrium and kinetic regimes by differential scanning calorimetry (DSC). For equilibrium experiments, the drugs were introduced during preparation of the model membrane. In kinetic studies, one of the drugs was added to the DPPC membrane already containing the other drug, and the effects of drug-membrane interactions were monitored in real-time regime. It was found that tilorone and DMSO had opposite effects on the membrane melting temperature, which were non-additive under joint introduction of these drugs. Analysis of kinetics of DSC profiles under drugs introduction allowed us to discriminate two processes in drug-membrane interactions with different characteristic times, i.e., drug sorption onto the membrane (minutes) and drug diffusion through stacks of lipid bilayers (hours). It was established that 0.1 mol% DMSO effectively enhanced membrane penetration for tilorone with the rate of tilorone diffusion being dependent upon the scheme of drugs administration. A model was proposed describing how sorption of a dopant onto lipid membrane could affect the membrane permeability for other dopants. Conditions were determined for enhancement of membrane permeability, as it was observed for DPPC/DMSO/tilorone system.