Possible molecular basis for the pharmacokinetics and pharmacodynamics of three membrane-active drugs: propranolol, nimodipine and amiodarone.

The interactions of propranolol, nimodipine, and amiodarone with membrane lipids were examined in an effort to explain their different pharmacokinetic and pharmacodynamic properties. Propranolol and nimodipine, which bind with high affinity to plasmalemmal beta-adrenergic and calcium channel receptors, respectively, have membrane partition coefficients of approximately 1200 and 5000 and are readily washed out of membranes with which they had been equilibrated. X-ray and neutron diffraction studies showed that after partitioning into lipid membranes, both propranolol and nimodipine are located approximately 6 A from the phosphate headgroup region of the membrane bilayer, near the hydrocarbon core/water interface. Amiodarone, which blocks Na and K channels with less site specificity than propranolol and nimodipine, has a much higher partition coefficient of approximately 1,000,000, resists washout from membrane bilayers, and is located deeper in the membrane, approximately 12 A from the phosphate headgroup region of the bilayer, nearer to the terminal methyl groups of the fatty acyl chains. The shorter durations of clinical action of propranolol and nimodipine may be related to the reversibility of their interactions with the region of the bilayer exposed to the aqueous media near the hydrocarbon core/water interface, whereas the much longer duration of clinical action of amiodarone may reflect a location more deeply within the fatty acyl region of the bilayer where this hydrophobic drug interacts avidly with the hydrocarbon core of the membrane.