The protonation equilibrium and hydrophobic character of lidocaine were characterized by its pKa and the octanol:buffer partition coefficients of the charged (P+) and neutral (Po) drug species. These measurements were accomplished by ultraviolet spectrophotometry of pure lidocaine HCl solutions at different temperatures, ionic strengths, and buffer concentrations. Corroboration of the pKa determination by the potentiometric method and of the partition coefficients by gas chromatography validated the general application of the spectrophotometric technique. The pKa increased with decreasing temperature (7.61 +/- 0.06 at 36 degrees C; 7.94 +/- 0.04 at 26 degrees C, in water; mean +/- SD), increasing ionic strength (8.06 +/- 0.02 at 26 degrees C in 0.165 M NaCl) and increasing buffer capacity (8.28 +/- 0.06 at 25 degrees C in 0.15 M NaCl + 20 mM buffer). Octanol:buffer partition coefficients for both the protonated and the neutral species (expressed as mole fractions) increased upon warning: 0.55 +/- 0.04 and 2666 +/- 202, respectively, at 25 degrees C, and 0.75 +/- 0.09 and 3210 +/- 272, respectively, at 36 degrees C. Ionic strength and buffer concentration had no significant effect on either P value. The increase in pKa at lower temperatures coupled with the decreased partition coefficients resulted in a nearly constant concentration of the protonated species in octanol as the system was cooled, whereas the concentration of the neutral species fell by more than 80%. This finding may explain the large increase in the impulse blocking potency of lidocaine observed upon nerve cooling, if the protonated anesthetic species is the more active form of the drug competing with the neutral species for a common binding site.