title: Probing the combined effect of flunitrazepam and lidocaine on the stability and organization of bilayer lipid membranes. A differential scanning calorimetry and dynamic light scattering study.
abstract: Combined effects of flunitrazepam (FNZ) and lidocaine (LDC) were studied on the thermotropic equilibrium of dipalmitoyl phosphatidylcholine (dpPC) bilayers. This adds a thermodynamic dimension to previously reported geometric analysis in the erythrocyte model. LDC decreased the enthalpy and temperature for dpPC pre- and main-transitions (ΔHp, ΔHm, Tp, Tm) and decreased the cooperativity of the main-transition (ΔT(1/2,m)). FNZ decreased ΔHm and, at least up to 59 μM, also decreased ΔHp. In conjunction with LDC, FNZ induced a recovery of ∆T(1/2,m) control values and increased ΔHm even above the control level. The deconvolution of the main-transition peak at high LDC concentrations revealed three components possibly represented by: a self-segregated fraction of pure dpPC, a dpPC-LDC mixture and a phase with a lipid structure of intermediate stability associated with LDC self-aggregation within the lipid phase. Some LDC effects on thermodynamic parameters were reverted at proper LDC/FNZ molar ratios, suggesting that FNZ restricts the maximal availability of the LDC partitioned into the lipid phase. Thus, beyond its complexity, the lipid-LDC mixture can be rationalized as an equilibrium of coexisting phases which gains homogeneity in the presence of FNZ. This work stresses the relevance of nonspecific drug-membrane binding on LDC-FNZ pharmacological interactions and would have pharmaceutical applications in liposomal multidrug-delivery.
authors.affiliation: Departamento de Química, FCEFyN, Instituto de Investigaciones Biológicas y Tecnológicas (IIBYT), CONICET-Universidad Nacional de Córdoba, Córdoba, Argentina. bcaruso@efn.uncor.edu
authors.forename: Benjamín
authors.initials: B
authors.lastname: Caruso
authors.forename: Julieta M
authors.initials: JM
authors.lastname: Sánchez
authors.forename: Daniel A
authors.initials: DA
authors.lastname: García
authors.forename: Eneida
authors.initials: E
authors.lastname: de Paula
authors.forename: María A
authors.initials: MA
authors.lastname: Perillo
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000378:metabolism; D002152:Calorimetry, Differential Scanning; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D004347:Drug Interactions; D005445:Flunitrazepam / Q000494:pharmacology*; D008012:Lidocaine / Q000494:pharmacology*; D008027:Light; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D012542:Scattering, Radiation; D013816:Thermodynamics
chemical_list: D008051:Lipid Bilayers; D015060:1,2-Dipalmitoylphosphatidylcholine; D005445:Flunitrazepam; D008012:Lidocaine