How Warfarin鈥檚 Structural Diversity Influences Its Phospholipid Bilayer Membrane Permeation

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• 作者：Bj枚rn C. G. Karlsson ; Gustaf D. Olsson ; Ran Friedman ; Annika M. Rosengren ; Henning Henschel ; Ian A. Nicholls
• 刊名：The Journal of Physical Chemistry B
• 出版年：2013
• 出版时间：February 28, 2013
• 年：2013
• 卷：117
• 期：8
• 页码：2384-2395
• 全文大小：810K
• 年卷期：v.117,no.8(February 28, 2013)
• ISSN：1520-5207

文摘

The role of the structural diversity of the widely used anticoagulant drug warfarin on its distribution in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer membranes was investigated using a series of both restrained (umbrella sampling) and unrestrained molecular dynamics simulations. Data collected from unrestrained simulations revealed favorable positions for neutral isomers of warfarin, the open side chain form (OCO), and the cyclic hemiketal (CCO), along the bilayer normal close to the polar headgroup region and even in the relatively distant nonpolar lipid tails. The deprotonated open side chain form (DCO) was found to have lower affinity for the DOPC bilayer membrane relative to the neutral forms, with only a small fraction interacting with the membrane, typically within the polar headgroup region. The conformation of OCO inside the lipid bilayer was found to be stabilized by intramolecular hydrogen bonding thereby mimicking the structure of CCO. Differences in free energies, for positions of OCO and CCO inside the bilayer membrane, as compared to positions in the aqueous phase, were 鈭?7 and 鈭?46 kJ路mol^鈥?. Kinetic analysis based on the computed free energy barriers reveal that warfarin will diffuse through the membranes within hours, in agreement with experimental results on warfarin鈥檚 accumulation in the plasma, thus suggesting a passive diffusion mechanism. We propose that this membrane transport may be an isomerization-driven process where warfarin adapts to the various local molecular environments encountered under its journey through the membrane. Collectively, these results improve our understanding of the influence of warfarin鈥檚 structural diversity on the drug鈥檚 distribution and bioavailability, which in turn may provide insights for developing new formulations of this important pharmaceutical to better address its narrow therapeutic window.