Structure and location of amiodarone in a membrane bilayer as determined by molecular mechanics and quantitative x-ray diffraction

Abstract

Amiodarone is a drug used in the treatment of cardiac arrhythmias and is believed to have a persistent interaction with cellular membranes. This study sought to examine the structure and location of amiodarone in a membrane bilayer. Amiodarone has a high membrane partition coefficient on the order of 10(6). Small angle x-ray diffraction was used to determine the position of the iodine atoms of amiodarone in dipalmitoylphosphatidylcholine (DPPC) lipid bilayers under conditions of low temperature and hydration where the DPPC bilayer is in the gel state. The time-averaged position of the iodine atoms was determined to be approximately 6 A from the center (terminal methyl region) of the lipid bilayer. A dielectric constant of kappa = 2, which approximates that of the bilayer hydrocarbon core region, was used in calculating a minimum energy structure for membrane-bound amiodarone. This calculated structure when compared with the crystal structure of amiodarone demonstrated that amiodarone could assume a conformation in the bilayer significantly different from that in the crystal. The results reported here are an attempt to correlate the position of a membrane-active drug in a lipid bilayer with its time-averaged conformation. This type of analysis promises to be of great use in the design of drugs with greater potency and higher specificity.

Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels

“…C demonstrates a systematic investigation of the voltage dependence of amiodarone block. Protocol: holding -80 mV; blocking pulse -60 mV to 80 mV in 10-mV increments (21 s); followed by the constant second protocol to determine the amount of block: step 1 with -120 mV (400 ms), step 2 with 40 mV (50 ms), step 3 with -120 mV (110 ms) membrane partition coefficient Trumbore et al 1988). This high membrane partition results in its slow pharmacokinetic and pharmacodynamic action.…”

Amiodarone Protects Cardiac Myocytes Against Oxidative Injury by its Free Radical Scavenging Action

“…15 However, this drug is a highly lipophilic compound, 16 suggesting a high affinity of this drug to the plasma membranes. 17 Therefore, it is conceivable that an effective tissue concentration level of amiodarone for exerting the cardioprotective action may be attainable when administered in vivo.…”

Comparing the Lipid Membrane Affinity and Permeation of Drug-like Acids: The Intriguing Effects of Cholesterol and Charged Lipids

“…9 revealed the apparent rate constants (Eqs. [26][27][28][29] for a symmetrical bilayer with equal conditions in the outer and inner aqueous phases.…”