The interplay of membrane fluidity, acyl chain order and area per lipid on the partitioning of two antidepressants paroxetine and sertraline

• Published in: Soft matter Vol. 19; no. 29; pp. 5527 - 5537
• Main Authors: Ngo, Dat T. N, Ho, Tho H, Huynh, Lam K, Nguyen, Trang T
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 26.07.2023
• Subjects: Antidepressants; Antidepressive Agents; Fluidity; Humans; Lipid Bilayers - metabolism; Lipids; Membrane composition; Membrane Fluidity; Membranes; Mental depression; Mental disorders; Molecular dynamics; Order parameters; Paroxetine; Partitioning; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin uptake inhibitors; Sertraline; Spectrophotometry; Viscosity
• ISSN: 1744-683X; 1744-6848
• DOI: 10.1039/d3sm00462g

Selective serotonin reuptake inhibitors (SSRIs) are among the popular drugs for treating depression and mental disorders. Membrane fluidity has previously been considered as the main factor in modulating the membrane partitioning of SSRIs, while other biophysical properties, such as the acyl chain order and area per lipid, were often neglected. Varying the lipid membrane composition and temperature can significantly modify the physical phase and, in turn, affect its fluidity, acyl chain order and area per lipid. Here, we investigate the role of membrane fluidity, acyl chain order and area per lipid in the partitioning of two SSRIs, paroxetine (PAX) and sertraline (SER). The model membranes were either POPC : SM (1 : 1 mol ratio) or POPC : SM : Chol (1 : 1 : 1 mol ratio) and studied in the temperature range of 25-45 °C. The order parameters and area per lipid in the two lipid mixtures were calculated using molecular dynamics simulations. The membrane partitioning of PAX and SER was determined via second derivative spectrophotometry. In a lower temperature range (25-32 °C), membrane fluidity favors the SSRI partitioning into L o /L d POPC:SM:Chol. In a higher temperature range (37-45 °C), the interplay between membrane fluidity, acyl chain order and area per lipid favors drug partitioning into L d POPC:SM. The findings offer indication for the inconsistent distribution of SSRIs in tissues as well as the possible interaction of SSRIs with lipid domains and membrane-bound proteins. The interplay between the lipid phase, area per lipid, and acyl chain order dictates differential membrane partitioning of SSRIs.