The dissimilar interactions of the calcium antagonist flunarizine with different phospholipid classes and molecular species: a differential scanning calorimetry study.

The influence of the class IV calcium antagonist flunarizine on the phase behaviour of different species of the major phospholipid classes of mammalian plasma membranes has been examined using differential scanning calorimetry. We show that it has the ability to substantially influence the phase behaviour of phospholipids. Flunarizine significantly influences the gel to liquid-crystalline transition temperature of phosphatidylserines whilst having little effect on those of the phosphatidylethanolamines tested. The liquid-crystalline to inverted hexagonal phase transition of phosphatidylethanolamines is, however, strongly induced by the presence of flunarizine. Examination of the effect of flunarizine on the phase behaviour of different phosphatidylcholine species revealed an acyl-chain dependent influence. Dissimilar results with phosphatidylcholines, phosphatidylethanolamines and phosphatidylserines reveal different locations and ionization states for the drug in the different phospholipid bilayers. These results not only indicate an essential role for the ionization state of the drug in determining drug-phospholipid interactions but also the role of the phospholipid in determining the ionization state of the drug and have important implications for drug-membrane interactions demonstrating that drug interaction with one phospholipid may bear no relation whatsoever to its interaction with another.