Interaction of fluoxetine with phosphatidylcholine liposomes.
Fluoxetine (Prozac) is one of the latest of a new generation of antidepressants, approved by FDA in 2002. The interactions of fluoxetine with multilamellar liposomes of pure phosphatidylcholine (PC) or containing cholesterol 10% molar were studied as a function of the lipid chain lengths, using differential scanning calorimetry and spin labelling EPR techniques. The DSC profiles of the gel-to-fluid state transition of liposomes of DMPC (C14:0) are broadened and shifted towards lower temperatures at increasing dopant concentrations and, with less than 10% fluoxetine, any detectable transition is destroyed. The broadened profiles and the lowered transition temperatures demonstrate that both the size and the packing of the cooperative units undergoing the transition are modified by fluoxetine, leading to a looser and more flexible bilayer. No phase separation was observed. The effects of fluoxetine on the thermotropic phase behaviour of DPPC (C16:0) and, even more, of DSPC (C18:0) are different from that of DMPC. In fact, in the former cases, two peaks appeared at increasing dopant concentrations, suggesting the occurrence of a phase separation phenomenon, which is a sign of a binding of fluoxetine in the phosphate region. In cholesterol containing membranes, fluoxetine, even at low concentrations, leads to a general corruption of the membrane, both in terms of packing and cooperativity, and the formation of any new phase is no longer observable. EPR spectra reflect the disordered motion of acyl chains in the bilayer. It was found that fluoxetine lowers the order of the lipid chains mainly in correspondence of the fifth carbon position of SASL, indicating a possible accumulation near the interfacial region.
Momo
Federico
F
Department of Physical Chemistry, University of Venice, Dorsoduro, 2137-30123 Venezia, Italy. momo@unive.it
Fabris
Sabrina
S
Stevanato
Roberto
R
D001665:Binding Sites; D002152:Calorimetry, Differential Scanning; D002244:Carbon / Q000737:chemistry; D016503:Drug Delivery Systems; D004578:Electron Spin Resonance Spectroscopy; D005473:Fluoxetine / Q000008:administration & dosage / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D044367:Phase Transition; D010710:Phosphates / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry*; D013696:Temperature
D008081:Liposomes; D010710:Phosphates; D010713:Phosphatidylcholines; D005473:Fluoxetine; D002244:Carbon