title: A new look at the hemolytic effect of local anesthetics, considering their real membrane/water partitioning at pH 7.4.
abstract: The interaction of local anesthetics (LA) with biological and phospholipid bilayers was investigated regarding the contribution of their structure and physicochemical properties to membrane partition and to erythrocyte solubilization. We measured the partition into phospholipid vesicles-at pH 5.0 and 10.5-and the biphasic hemolytic effect on rat erythrocytes of: benzocaine, chloroprocaine, procaine, tetracaine, bupivacaine, mepivacaine, lidocaine, prilocaine, and dibucaine. At pH 7.4, the binding of uncharged and charged LA to the membranes was considered, since it results in an ionization constant (pK(app)) different from that observed for the anesthetic in the aqueous phase (pK(w)). Even though it occurred at a pH at which there is a predominance of the charged species, hemolysis was greatly influenced by the uncharged species, revealing that the disrupting effect of LA on these membranes is mainly a consequence of hydrophobic interactions. The correlation between the hemolytic activity and the LA potency shows that hemolytic experiments could be used for the prediction of activity in the development of new LA molecules.
authors.affiliation: Departamento de Bioquímica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), CP 6109, Campinas,SP 13083-970, Brazil.
authors.forename: Sônia V P
authors.initials: SV
authors.lastname: Malheiros
authors.forename: Luciana M A
authors.initials: LM
authors.lastname: Pinto
authors.forename: Luciane
authors.initials: L
authors.lastname: Gottardo
authors.forename: Daniela K
authors.initials: DK
authors.lastname: Yokaichiya
authors.forename: Leonardo F
authors.initials: LF
authors.lastname: Fraceto
authors.forename: Nilce C
authors.initials: NC
authors.lastname: Meirelles
authors.forename: Eneida
authors.initials: E
authors.lastname: de Paula
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000586:Amination; D000779:Anesthetics, Local / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001566:Benzocaine / Q000737:chemistry / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000737:chemistry* / Q000187:drug effects*; D004987:Ethers / Q000737:chemistry / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D007477:Ions / Q000737:chemistry; D051379:Mice; D015394:Molecular Structure; D014867:Water / Q000737:chemistry*
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D004987:Ethers; D007477:Ions; D014867:Water; D001566:Benzocaine