Pharmacokinetics of the Enantiomers of Bupivacaine Following Intravenous Administration of the Racemate

1. The pharmacokinetics of R(+)-bupivacaine and S(-)-bupivacaine were investigated following a 10 min intravenous infusion of the racemate (dose 30 mg) in 10 healthy males. 2. The fractions unbound of R(+)- and S(-)-bupivacaine in pre-dose plasma were determined for each subject after in vitro addition of rac-bupivacaine (concentration of each enantiomer: approximately 300 ng ml-1). 3. The total plasma clearance of R(+)-bupivacaine (mean +/- s.d.: 0.395 +/- 0.076 l min-1) was greater (P < 0.0001) than that of S(-)-bupivacaine (0.317 +/- 0.067 l min-1). The volumes of distribution of R(+)-bupivacaine at steady state (84 +/- 29 l) and during the terminal log-linear phase (117 +/- 47 l) were larger (P < 0.0002) than those of S(-)-bupivacaine (54 +/- 20 l and 71 +/- 34 l, respectively). The terminal half-life (210 +/- 95 min) and mean residence time (215 +/- 74 min) of R(+)-bupivacaine were longer than those of S(-)-bupivacaine (157 +/- 77 min, P < 0.01, and 172 +/- 55 min, P < 0.02, respectively). 4. The free percentage of R(+)-bupivacaine (6.6 +/- 3.0 %) was greater (P < 0.0002) than that of S(-)-bupivacaine (4.5 +/- 2.1 %). 5. The plasma clearance of unbound R(+)-bupivacaine (7.26 +/- 3.60 1 min-1) was smaller (P < 0.01) than that of S(-)-bupivacaine (8.71 +/- 4.27 l min-1). Volumes of distribution based on unbound R(+)-bupivacaine concentrations (Vuss: 1576 +/- 934 l; Vu: 2233 +/- 1442 l) did not differ from those of S(-)-bupivacaine (Vuss: 1498 +/- 892 l; Vu: 1978 +/- 1302 l). 6. The enantioselective systemic disposition of bupivacaine can to a large extent be attributed to differences in the degree of plasma binding of the enantiomers.