Abstract

The ability of a therapeutic agent to cross lipid membranes is crucial in terms of its pharmacodynamic properties. In this study, the partitioning of venlafaxine, a recently introduced antidepressant in the class of serotonin and norepinephrine reuptake inhibitors (SNRIs), into large unilamellar vesicles (LUVs) composed of zwitterionic 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and negatively charged 1,2-dioleoyl-sn-glycero-3-phosphoglycerol (DOPG) was investigated using second derivative spectrophotometry. The partition coefficients of venlafaxine into DOPC and DOPG LUVs were determined at various temperatures (25, 37, and 45 °C) and pH values (7.4 and 9.5). The results indicate a positive correlation between temperature and the extent of venlafaxine partitioning into both zwitterionic and charged lipid bilayers; furthermore, the drug preferentially partitions into the zwitterionic lipid bilayer at all investigated temperatures. Thermodynamic analysis further reveals that the membrane partitioning of venlafaxine aligns with the classical hydrophobic effect. Varying the proportion of neutral versus charged venlafaxine further indicates that both electrostatic and hydrophobic interactions modulate the partitioning of the drug into the zwitterionic neutral bilayer. In the case of the negatively charged bilayer, electrostatic interactions are predominant over hydrophobic ones in modulating the partitioning of venlafaxine. These findings provide further insights into SNRI–lipid membrane interactions, potentially leading to the development of more effective antidepressants.