Binding of the calcium antagonist flunarizine to phosphatidylcholine bilayers: charge effects and thermodynamics.
We have examined the partitioning/transfer of the Ca2+ antagonist flunarizine from the aqueous phase into phospholipid bilayers. We show that the binding of the cationic amphiphilic drug flunarizine to phospholipid bilayers displays traditional linear concentration-dependent characteristics once unmasked of electrostatic effects. The coefficient for the binding/partitioning of flunarizine to phosphatidylcholine was found to be 28700 M-1, supporting the notion that this drug may be particularly membrane-active. The thermodynamics of the partitioning/transfer process have also been studied using high-sensitivity titration calorimetry. Binding was found to be predominantly enthalpy-driven with only a small entropic contribution; delta H = -22.1 kJ.mol-1 (-5.3 kcal.mol-1) at 27 degrees C. This is in conflict with established ideas of entropy-driven partitioning of drugs into phospholipid membranes as a result of the 'hydrophobic effect'. The strong enthalpic nature of binding is interpreted as being indicative of strong lipophilic interactions between the drug and the phospholipid phase.
Thomas
P G
PG
Institute of Molecular Biology and Medical Biotechnology, University of Utrecht, The Netherlands.
Seelig
J
J
D002151:Calorimetry; D002412:Cations; D004563:Electrochemistry; D005444:Flunarizine / Q000737:chemistry / Q000378:metabolism*; D008051:Lipid Bilayers / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism*; D013816:Thermodynamics
D002412:Cations; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D005444:Flunarizine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine