Membrane interaction of calcium channel antagonists modulated by cholesterol. Implications for drug activity

The interactions of lipophilic calcium channel antagonists with the membrane lipid bilayer are complex and highly dependent on membrane composition and structure. Variability in membrane lipid composition (e.g. cholesterol content, acyl chain saturation) can dramatically affect the membrane partitioning of calcium channel antagonists. The membrane binding properties of these drugs did not correlate with traditional measurements of drug lipophilicity, such as a simple hydrocarbon system (Table 2). These data indicate the need for directly measuring the binding of drug molecules to membranes in order to understand better certain pharmacological parameters, including bioavailability, under both normal and pathological conditions in which membrane composition is altered. The interaction of certain lipophilic amphipathic drugs with the membrane lipid bilayer may be an important component of their overall receptor binding mechanism. Specifically, the membrane bilayer may serve to concentrate and orient these drug molecules with respect to a hydrophobic receptor site at the protein receptor/membrane bilayer interface. Thus, the design of drugs which target membrane bound receptors should take into consideration the interaction of the drug molecule with the membrane lipid compartment. This understanding of drug/membrane interactions may lead to the development of drugs with more desirable pharmacokinetics, greater efficacy, and reduced side effects.