Mizogami Maki, Tsuchiya Hironori, Ueno Takahiro, Kashimata Masanori, Takakura Ko
Department of Anesthesiology, Asahi University School of Dentistry, Mizuho, Gifu, Japan.
Reg Anesth Pain Med. 2008 Jul-Aug;33(4):304-11. doi: 10.1016/j.rapm.2007.05.011.
S(-)-Bupivacaine has the pharmacotoxicological advantage over its antipode and racemate. The interaction with lipid membranes was compared between S(-)-, R(+)- and racemic bupivacaine.
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.
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.
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.
S(-)-布比卡因相较于其对映体和消旋体具有药物毒理学优势。比较了S(-)-、R(+)-布比卡因和消旋布比卡因与脂质膜的相互作用。
通过对应用1.0 - 5.0 mmol/L布比卡因立体异构体的膜制剂进行浊度和荧光偏振测量，确定布比卡因引起的膜性质变化。脂质体膜由1,2-二棕榈酰-sn-甘油-3-磷酸胆碱制成，不含或含有胆固醇（5至15 mol%），神经细胞模型膜由55 mol%不同磷脂和45 mol%胆固醇制成。通过反相高效液相色谱分析布比卡因的纯度和疏水相互作用。
S(-)-和R(+)-布比卡因在降低1,2-二棕榈酰-sn-甘油-3-磷酸胆碱膜的相变温度方面没有差异。S(-)-、R(+)-和消旋布比卡因使100 mol%的1,2-二棕榈酰-sn-甘油-3-磷酸胆碱脂质体膜紊乱，尽管立体异构体之间的效力难以区分。然而，通过向膜中添加胆固醇，膜紊乱效应表现出立体结构特异性，且随着胆固醇含量（0至15 mol%）的增加而增强。对映体区分效应既不是由对映体中的杂质引起，也不是与磷脂酰胆碱酰链的疏水相互作用所致。布比卡因使神经细胞模型膜紊乱，效力顺序为S(-)-对映体<消旋体<R(+)-对映体，这与其在神经和心脏通道抑制中的相对立体效力相似。在不含胆固醇 的膜中，膜紊乱的立体特异性消失。
布比卡因与含胆固醇的膜发生立体结构特异性相互作用，这与S(-)-布比卡因的临床特征一致。膜胆固醇似乎增加了脂质双层的手性，使其能够与S(-)-、消旋体和R(+)-布比卡因以不同方式相互作用。
