W. Caetano et al., Cooperativity of phospholipid reorganization upon interaction of dipyridamole with surface monolayers on water, BIOPHYS CH, 91(1), 2001, pp. 21-35
Results from various surface sensitive characterization techniques suggest
a model for the interaction of the piperidinopyrimidine dipyridamole (DIP)
- known as a vasodilator and inhibitor of P-glycoprotein associated multidr
ug resistance of tumor cells - with phospholipid monolayers in which the dr
ug is peripherally associated with the membrane, binding (up to) five phosp
holipids at a time. These multiple interactions are responsible for a very
strong association of the drug with the lipid monolayer even at exceedingly
low concentrations (similar to 0.2 mol%). Electrostatic interactions and h
ydrogen bonding are likely involved in the binding of DIP to DPPC, Cooperat
ive effects among the lipids are invoked to explain the macroscopically mea
surable changes of lipid monolayer properties even when only one out of 100
DPPC molecules is directly associated with a DIP molecule. A reversal of t
he observed changes upon drug association with the membrane as the DIP conc
entration surpasses a threshold concentration (c(crit) similar to0.5 mol%)
may be explained by cooperativity in a different context, the self-aggregat
ion of drug molecules. With its implications fur the interaction of DIP wit
h phospholipid films, this work provides a first approach to the explanatio
n of the high sensitivity of cell membranes to piperidinopyrimidine drugs o
n a molecular level. (C) 2001 Elsevier Science B.V. All rights reserved.