Effect of cholesterol on the partitioning of the antidepressant fluoxetine into lipid bilayers

Abstract

Cholesterol is a key component of all mammalian cell membranes; therefore, it is often included in the lipid formulation used in pharmacological studies. In this study, the effect of cholesterol on the partitioning of the antidepressant fluoxetine into the large unilamellar vesicles (LUVs) composed of zwitterionic 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), anionic 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG), di-unsaturated 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or mono-unsaturated 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC) was evaluated using second derivative spectrophotometry to gain insights into the mechanism of action of fluoxetine. The presence of 28 mol% cholesterol was found to facilitate the partitioning of fluoxetine into DPPC and DPPG liposomes whereas inhibit that into DOPC and SOPC liposomes. Moreover, due to the electrostatic attraction between positively charged fluoxetine and negatively charged DPPG, fluoxetine partitioned to a greater extent into DPPG LUVs as compared to that into the zwitterionic DPPC LUVs. Additionally, it was found that the higher level of unsaturation degree in DOPC liposomes allowed more fluoxetine partitioning than the mono-unsaturated SOPC liposomes, regardless the presence of cholesterol or not. These results obtained from this study suggest the therapeutic action of fluoxetine could be strongly influenced by its interaction with the lipid membranes. Keywords: Fluoxetine Cholesterol Phospholipids Partition coefficient Second derivative spectrophotometry