The pharmacokinetics of R(-)-mepivacaine and S(+)-mepivacaine were investigated in 10 healthy volunteers. The volunteers received racemic mepivacaine, hydrochloride (dose 60 mg) via a 10-min intravenous infusion. Blood samples were collected at gradually increasing intervals until 8 h after the start of the infusion. Plasma concentrations of the enantiomers were determined with a stereoselective high-performance liquid chromatographic (HPLC) method. Unbound fractions of the enantiomers were determined using equilibrium dialysis. The unbound fraction of R(-)-mepivacaine (mean +/- SD: 35.6% +/- 4.5%) was larger (P < 0.0001) than that of S(+)-mepivacaine (25.1% +/- 4.6%). The total plasma clearance and steady-state volume of distribution of R(-)-mepivacaine, based on total plasma concentrations (total plasma clearance [CL] = 0.79 +/- 0.12 L/min; volume of distribution at steady state [VSS] = 103 +/- 14 L) as well as on unbound plasma concentrations (plasma clearance of unbound drug [CLu] = 2.24 +/- 0.30 L/min; volume of distribution of unbound drug at steady state [Vuss] = 290 +/- 32 L), were larger (P < 0.0001) than those of S(+)-mepivacaine (CL = 0.35 +/- 0.06 L/min; Vss = 57 +/- 7 L; CLu = 1.43 +/- 0.24 L/ min; Vuss = 232 +/- 30 L). The terminal half-life (t1/2,Z) and mean residence time (MRT) of R(-)-mepivacaine (t1/2,Z = 113 +/- 17 min; MRT = 131 +/- 15 min) were shorter than those of S(+)-mepivacaine (t1/2,Z = 123 +/- 20 min, P < 0.02; MRT = 165 +/- 24 min, P < 0.0001). This study demonstrated a marked difference in the pharmacokinetics of the enantiomers of mepivacaine. The stereoselectivity can be partially explained by a difference in the plasma protein binding of the enantiomers.