Thermodynamics of selective serotonin reuptake inhibitors partitioning into 1,2-dioleoyl-sn-glycero-3-phosphocholine bilayers

Knowledge of thermodynamics of lipid membrane partitioning of amphiphilic drugs as well as their binding site within the membrane are of great relevance not only for understanding the drugs' pharmacology but also for the development and optimization of more potent drugs. In this study, the interaction between two representatives of selective serotonin reuptake inhibitors, including paroxetine and sertraline, and large unilamellar vesicles (LUVs) composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) was investigated by second derivative spectrophotometry and Fourier transform infrared spectroscopy (FTIR) to determine the driving force of the drug partitioning across lipid membranes. It was found that temperature increase from 25 to 42 °C greatly enhanced the partitioning of paroxetine and sertraline into DOPC LUVs, and sertraline intercalated into the lipid vesicles to a greater extent than paroxetine in the temperature range examined. The partitioning of both drugs into DOPC LUVs was a spontaneous, endothermic and entropy-driven process. FTIR measurements suggested that sertraline could penetrate deeply into the acyl tails of DOPC LUVs as shown by the considerable shifts in the lipid's CH(2) and C[double bond, length as m-dash]O stretching modes induced by the drug. Paroxetine, however, could reside closer to the head groups of the lipid since its presence caused a larger shift in the PO(2)(−) bands of DOPC LUVs. The findings reported here provide valuable insights into the influence of small molecules' chemical structure on their molecular interaction with the lipid bilayer namely their possible binding sites within the lipid bilayer and their thermodynamics profiles of partitioning, which could benefit rational drug design and drug delivery systems.