Interaction of Antiinflammatory Drugs with EPC Liposomes: Calorimetric Study in a Broad Concentration Range

Abstract

Isothermal titration calorimetry was used to characterize and quantify the partition of indomethacin and acemetacin between the bulk aqueous phase and the membrane of egg phosphatidylcholine vesicles. Significant electrostatic effects were observed due to binding of the charged drugs to the membrane, which implied the use of the Gouy-Chapman theory to calculate the interfacial concentrations. The binding/partition phenomenon was quantified in terms of the partition coefficient (K(p)), and/or the equilibrium constant (K(b)). Mathematical expressions were developed, either to encompass the electrostatic effects in the partition model, or to numerically relate partition coefficients and binding constants. Calorimetric titrations conducted under a lipid/drug ratio >100:1 lead to a constant heat release and were used to directly calculate the enthalpy of the process, DeltaH, and indirectly, DeltaG and DeltaS. As the lipid/drug ratio decreased, the constancy of reaction enthalpy was tested in the fitting process. Under low lipid/drug ratio conditions simple partition was no longer valid and the interaction phenomenon was interpreted in terms of binding isotherms. A mathematical expression was deduced for quantification of the binding constants and the number of lipid molecules associated with one drug molecule. The broad range of concentrations used stressed the biphasic nature of the interaction under study. As the lipid/drug ratio was varied, the results showed that the interaction of both drugs does not present a unique behavior in all studied regimes: the extent of the interaction, as well as the binding stoichiometry, is affected by the lipid/drug ratio. The change in these parameters reflects the biphasic behavior of the interaction-possibly the consequence of a modification of the membrane's physical properties as it becomes saturated with the drug.

Interaction of the Macrolide Antibiotic Azithromycin with Lipid Bilayers: Effect on Membrane Organization, Fluidity, and Permeability

“…One of the major goals of current research in biophysics is to characterize the fundamental interactions between drugs or macromolecules and multimolecular structures such as lipid monolayers or bilayers (30)(31)(32)(33)(34)(35)(36). Formation of lateral microdomains is particularly important in this respect both from the structural and functional points of view.…”

Screening for the Drug–Phospholipid Interaction: Correlation to Phospholipidosis

“…The former emphasizes the correlation for the detection of the difference between very weak and very strong PLD inducers, and is more strongly affected by single outliers, whereas the latter emphasizes the correlation for the detection of the differences in potency over a wide interval (Figure 11). In linear correlations the EC 50 values of Morelli et al [205] reveal best correlation with PLD index, and c 2 data from Nioi et al [194] and Kasahara et al [192] have their second-best correlation with PLD index. The data reported by Bhandari et al [195] show the best and second-best correlations to the data sets of Kasahara et al [192] and Nioi et al [194] ( Table 2).…”

“…In general, the correlation to PLD index is much better for values that reflect the concentrations of drugs required to inflict significant PLD, that is, c 2 and EC 50 . Another similar value is the A 50 value of Bhandari et al, [195] who also used a fluorescent lipid accumulation assay, collected the data using three different cell lines (HepG2 cells, rat hepatocytes, and rhesus monkey hepatocytes), and found significant differences between the cell lines for a few of the drugs.…”

“…Usually at least a mole percent of drug is needed to have a significant impact on the physical properties of bilayers, [49][50][51] although significant effects of lateral heterogeneity have been reported at a few tenths of a mole percent. [52,53] Therefore, the required total concentration in a cell compartment is expected to be in the high-micromolar to lowmillimolar range, in contrast to the low-micromolar concentration range in low-lipid experimental systems such as model membranes or dilute cell cultures (see Supporting Information).…”

Development and characterisation study of liposomes-encapsulated piroxicam.

“…Pharmacokinetic study has demonstrated that the hydrophobic piroxicam has a slow absorption via oral route, which resulted in low bioavailability of the drug and delayed the onset of its therapeutics effects [7]. Due to the potential modification of drug's bioavailability and therapeutic index using liposomal technology, the strategy to entrap piroxicam in liposomes is therefore deemed important in pharmaceutical field [8,9]. Over the years, numerous techniques and procedures have been described to prepare liposome-encapsulated drugs with different sizes and characteristics.…”