Membrane pathways for drug/ion channel interactions: Molecular basis for pharmacokinetic properties

This review focuses on the interactions of certain classes of drugs that are known to bind to membrane‐bound ion channel/receptors. The concepts described here have broad applications to various ion channels as well as membrane bound receptors that are not ion channels such as the superfamily of G protein coupled receptors. Since data spanning from the molecular to the clinical field currently exists for drugs that bind to the voltage gated calcium channel, this review will highlight this rather narrow scope. It is to be appreciated that the concepts, as described, may have applicability to other membrane‐bound receptors. The focus will be on the calcium channel antagonist drugs of the 1,4 dihydropyridine type that bind to the L type calcium channel. Clearly an evolution in their molecular design has been brought to a point where these molecules are not only amphiphilic but increasingly lipophilic. Simply stated, this means that these drugs can readily transport across cell membranes accessing both hydrophilic and hydrophobic environments, although they have also become more soluble in the membrane bilayer. From an equilibrium point of view these molecules prefer to reside in the lipid bilayer hydrocarbon core; from a kinetic point of view they spend more time, on average, solvated within membranes than outside membranes, but their rates of entry into and exit from membranes do not appear to be related solely to their intramembranal equilibrium concentration. This biophysical understanding appears not only to define the molecular pathways for drug binding to the calcium channel receptor, but also to explain differences in the overall clinical pharmacokinetics observed for different drugs in this class. The potency of calcium antagonists is primarily related to their binding affinity to the calcium channel with a variable degree of dependency on the solvation of the drug in the membrane. The pharmacokinetic profile of calcium antagonists, although influenced to some degree by interactions with the target receptor, appears to be largely dictated by their interactions with the cell membranes at the molecular level. These interactions are distinctly different for each calcium antagonist but they can be classified into a few subgroups to explain drug onset and duration of action. © 1994 Wiley‐Liss, Inc.