A quantitative approach to the determination of drug release from reverse-phase evaporation lipid vesicles. The influence of sodium ion-pair formation on warfarin partitioning and permeability

Cools, Ardouin A.; Janssen, Lambert H.M.

doi:10.1016/0378-5173(84)90180-7

Cited by 2 publications

(1 citation statement)

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“…The authors explained this correlation to be driven by an ion-pairing mechanism, in particular between the deprotonated form of warfarin and sodium ions, which facilitates the passive diffusion of charged warfarin species across the membrane. The importance of the formation of the sodium ion-pairing of the deprotonated open side chain form of warfarin for membrane permeation was also suggested by Cools and Janssen after studying the effect on sodium ion concentration on permeation of warfarin across reverse-phase evaporation (REV) lipid vesicles of dipalmitoylphosphatidylcholine (DPPC) at pH 11.5. Although the authors in a previous paper had reported the importance of sodium ion concentration for warfarin–membrane permeation, the later study involving DPPC REVs demonstrated no clear correlation.…”

Section: Introductionmentioning

confidence: 91%

How Warfarin’s Structural Diversity Influences Its Phospholipid Bilayer Membrane Permeation

et al. 2013

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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 -97 and -146 kJ·mol(-1). 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's 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's structural diversity on the drug's distribution and bioavailability, which in turn may provide insights for developing new formulations of this important pharmaceutical to better address its narrow therapeutic window.

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Section: Introductionmentioning

confidence: 91%