Ionization and adsorption of a series of local anesthetics in detergent micelles: studies of drug fluorescence

S Desai, T Hadlock, C Messam, R Chafetz and G Strichartz

Anesthesia Research Laboratories, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts.

The goal of this study was to compare the behavior of structurally homologous local anesthetics (LAs) adsorbed to a simplified membrane model. Interactions of LAs with micelles made from negative and neutral detergents were assayed by drug fluorescence. Micellar:drug affinity, equivalent dielectric constant and pKa of bound LAs were assessed for procaine, tetracaine, procainamide, benzocaine and aminoparabenzyldiethylamine, a procaine homologue containing an alkyl chain instead of an ester bond. Shifts in maximum emission wavelength and changes in fluorescence intensity showed that 1) increased LA hydrophobicity (expressed as octanol:buffer partition coefficient) corresponded to increased affinity for all micelles; 2) protonated species of LA were bound more tightly than neutral species to negative micelles, but less tightly to unchanged micelles; 3) drugs with larger dipole moments (amide < ester < alkyl) bind less tightly to micelles than those with smaller dipoles; 4) Larger dipole moments of LAs also result in a larger equivalent dielectric constant around the micellar- bound LAs, meaning that the LA binds at a shallower depth from the micelle surface; and 5) binding the neutral micelles lowers the pKa but binding to negatively charged micelles raises the pKa (due to the concentrating effects of surface charge on H+). The results provide a picture of interfacial adsorption of LAs in a relatively simple system that should allow interrelation of the dipole field contributions to LA behavior in phospholipid bilayers.

Volume 271, Issue 1, pp. 220-228, 10/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

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