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Stereospecific interaction of bupivacaine enantiomers with lipid membranes.

Abstract：

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.

journal_name

Reg Anesth Pain Med

journal_title

Regional anesthesia and pain medicine

authors

Mizogami M,Tsuchiya H,Ueno T,Kashimata M,Takakura K

doi

10.1016/j.rapm.2007.05.011

subject

Has Abstract

pub_date

2008-07-01 00:00:00

pages

304-11

issue

eissn

1098-7339

issn

1532-8651

pii

S1098-7339(08)00124-7

journal_volume

pub_type

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Stereospecific interaction of bupivacaine enantiomers with lipid membranes.