Pharmacokinetics of bupivacaine enantiomers in sheep: influence of dosage regimen and study design.

Bupivacaine is used as a racemate. In previous studies the mean total body clearance of R(+)-bupivacaine was found to be greater than S(-)-bupivacaine by 65% after iv bolus dose of separate enantiomers and by 20% after iv infusion to steady state of racemate. The present studies were performed to determine whether different study designs using different iv dosage regimens could influence the pharmacokinetic parameters determined for either bupivacaine enantiomer. rac-Bupivacaine.HCl was administered iv to 6 adult Merino ewes by bolus, brief infusion, and prolonged infusion. Arterial blood concentrations of R(+)- and S(-)-bupivacaine were measured by enantioselective HPLC. These regimens consistently produced lower arterial blood concentrations of R(+)-bupivacaine than S(-)-bupivacaine due to R(+)-bupivacaine having a greater initial dilution volume by 16 (95% CI = 3-29)%, volume of distribution at steady state equilibrium by 32 (95% CI = 17-32)% and mean total body clearance by 28 (95% CI = 21-35)%. The slow half-life of R(+)-bupivacaine, however, was found to be 15 (95% CI = 0-31)% longer than that of S(-)-bupivacaine. The difference between enantiomers in mean total body clearance thus was similar to the previous study based upon infusion to steady state of rac-bupivacaine. Differences in pharmacokinetics attributable to the dosage regimen consisted of a greater mean total body clearance for R(+)-bupivacaine along with a smaller terminal half life with the bolus regimen and a longer half-life of S(-)-bupivacaine after prolonged infusion. Differences in pharmacokinetics between the bupivacaine enantiomers occurred consistently in both distribution and clearance but the magnitude of the effect was less than 50% in each case. Systematic differences in pharmacokinetics associated with the dosage regimen were found mainly in terminal half-life. Dosage regimen, thus, was found to influence the pharmacokinetic results found experimentally and is therefore a significant variable in its own right.