Amantadine partition and localization in phospholipid membrane: a solution NMR study

Quantification of membrane partition potential of drug compounds is of great pharmaceutical interest. Here, a novel approach combining liquid-state NMR diffusion measurements and fast-tumbling lipid/detergent bicelles is used to measure accurately the partition coefficient K-p of amantadine in phospholipid bilayers. Amantadine is found to have a strong membrane partition potential, with K-p of 27.6 in DMPC and 37.8 in POPC lipids. Electrostatic interaction also plays a major role in the drug's affinity towards biological membrane as introduction of negatively charged POPG dramatically increases its K-p. Saturation transfer difference experiments in small bicelles indicate that amantadine localizes near the negatively charged phosphate group and the hydrocarbon chain of bilayer lipid. The approach undertaken in this study is generally applicable for characterizing interactions between small molecules and phospholipid membranes. (C) 2004 Elsevier Inc. All rights reserved.