Thermal dependence of multidrug-resistant-modulator efficiency: a study in anionic liposomes

Area of Science:

• Pharmacology
• Biophysics
• Physical Chemistry

Background:

• Multidrug resistance (MDR) poses a significant challenge in treating diseases like cancer and infections.
• Lipophilic drugs can modulate MDR by interacting with cell membrane phospholipids.
• Tissue metabolic levels, which correlate with temperature, may influence the efficacy of MDR modulators.

Purpose of the Study:

• To investigate the correlation between the lipophilic drug's ability to reverse multidrug resistance (MDR) and tissue metabolic levels.
• To elucidate the role of drug-membrane interactions, specifically with phospholipids, in MDR reversal.
• To quantify the temperature-dependent permeation properties of MDR modulators.

Main Methods:

• Studied permeation properties of five MDR modulators using unilamellar liposomes and Sulphan blue dye leakage.
• Quantified dye leakage over a temperature range of 27-42°C.
• Analyzed the thermodynamic parameters (enthalpy, entropy, Gibbs free energy) of the permeation process.

Main Results:

• Dye leakage induced by modulators (Triton X-100, diltiazem, verapamil, thioacridine derivative, mepacrine) was temperature-dependent.
• Permeation ability (log(1/PD50)) decreased with increasing net electric charge (z) of the modulators.
• Passive dye leakage was an endothermic process favored by increased membrane disorder; higher temperatures enhanced this effect, particularly for charged compounds like mepacrine.

Conclusions:

• Drug-membrane interactions, influenced by drug charge and tissue temperature, are critical for MDR reversal.
• Higher metabolic levels (and thus temperatures) in tissues likely enhance MDR reversal through favorable drug-membrane interactions.
• The findings suggest a mechanism for optimizing MDR-modulator therapy based on physiological temperature and drug properties.