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 1 min(-1)) was greater (P < 0.0001) than that of S(-)-bupivacaine (0.317 +/- 0.067 1 min(-1)). The volumes of distribution of R(+)-bupivacaine at steady state (84 +/- 29 1) and during the terminal log-linear phase (117 +/- 47 1) were larger (P < 0.0002) than those of S(-)-bupivacaine (54 +/- 20 1 and 71 +/- 34 1, 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 1 min(-1)). Volumes of distribution based on unbound R(+)-bupivacaine concentrations (Vu(ss): 1576 +/- 934 1; Vu: 2233 +/- 1442 1) did not differ from those of S(-)-bupivacaine (Vu(ss): 1498 +/- 892 1; Vu: 1978 +/- 1302 1). 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.