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Stereospecific Interaction of Bupivacaine Enantiomers with Lipid Membranes
  1. Maki Mizogami, M.D., Ph.D.a,*,
  2. Hironori Tsuchiya, Ph.D.b,
  3. Takahiro Ueno, D.D.S.a,
  4. Masanori Kashimata, Ph.D.c and
  5. Ko Takakura, M.D., Ph.D.a
  1. aDepartment of Anesthesiology, Asahi University School of Dentistry, Mizuho, Gifu, Japan
  2. bDepartment of Dental Basic Education, Asahi University School of Dentistry, Mizuho, Gifu, Japan
  3. cDepartment of Dental Pharmacology, Asahi University School of Dentistry, Mizuho, Gifu, Japan.
  4. *Reprint requests: Maki Mizogami, M.D., Ph.D., Department of Anesthesiology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan. E-mail: makikai{at}


Background and Objectives: S(−)-Bupivacaine has the pharmacotoxicological advantage over its antipode and racemate. The interaction with lipid membranes was compared between S(−)-, R(+)- and racemic bupivacaine.

Methods: The bupivacaine-induced changes in membrane property were determined by turbidity and fluorescence polarization measurements of membrane preparations to which bupivacaine stereoisomers of 1.0-5.0 mmol/L were applied. Liposomal membranes were made of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine without or with cholesterol (5 to 15 mol%), and nerve cell model membranes of 55 mol% different phospholipids and 45 mol% cholesterol. The purity and hydrophobic interaction of bupivacaine were analyzed by reversed-phase high-performance liquid chromatography.

Results: Both S(−)- and R(+)-bupivacaine were not different in lowering the phase transition temperature of membrane 1,2-dipalmitoyl-sn-glycero-3-phosphocholine. S(−)-, R(+)- and racemic bupivacaine disordered 100 mol% 1,2-dipalmitoyl-sn-glycero-3-phosphocholine liposomal membranes, although the potency was indistinguishable between stereoisomers. By adding cholesterol to membranes, however, the membrane-disordering effects showed stereostructure-specificity that was enhanced with increasing the cholesterol content (0 to 15 mol%). The enantio-differentiating effects resulted from neither impurities in enantiomers nor hydrophobic interaction with phosphatidylcholine acyl chains. Bupivacaine disordered nerve cell model membranes with the potency being S(−)-enantiomer < racemate < R(+)-enantiomer, which resembled their relative stereopotency in nerve and cardiac channel inhibition. Membrane-disordering stereospecificity disappeared in the membranes without containing cholesterol.

Conclusions: Bupivacaine stereostructure-specifically interacts with membranes containing cholesterol, which is consistent with the clinical features of S(−)-bupivacaine. Membrane cholesterol appears to increase the chirality of lipid bilayers and enable them to interact with S(−)-, racemic and R(+)-bupivacaine differently.

  • Bupivacaine enantiomers
  • Stereospecific membrane interaction
  • Membrane disordering
  • Lipid composition

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  • Supported by a grant-in-aid for Scientific Research (C) 15592145 from JSPS and a research grant from the Miyata Scientific Research Foundation. Presented in part at the International Anesthesia Research Society (IARS) 80th Clinical and Scientific Congress, March 26, 2006, San Francisco, CA.