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(-)-b upivacaine by 65% after iv bolus dose of separate enantiomers and by 2 0% after iv infusion to steady state of racemate. The present studies were performed to determine whether different study designs using diff erent iv dosage regimens could influence the pharmacokinetic parameter s determined for either bupivacaine enantiomer. rac-Bupivacaine . HCl was administered iv to 6 adult Merino ewes by bolus, brief infusion, a nd prolonged infusion. Arterial blood concentrations of R(+)- and S(-) -bupivacaine were measured by enantioselective HPLC. These regimens co nsistently produced lower arterial blood concentrations of R(+)-bupiva caine than S(-)-bupivacaine due to R(+)-bupivacaine having a greater i nitial 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(+)-bupivacain e, however, was found to be 15 (95% CI=0-31)% longer than that of S(-) -bupivacaine. The difference between enantiomers in mean total body cl earance thus was similar to tire previous study based upon infusion to steady state of rac-bupivacaine. Differences in pharmacokinetics attr ibutable 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 aft er prolonged infusion. Differences in pharmacokinetics between the bup ivacaine enantiomers occurred consistently in both distribution and cl earance but the magnitude of the effect was less than 50% in each case . Systematic differences in pharmacokinetics associated with the dosag e regimen were found mainly in terminal half-life. Dosage regimen, thu s, was found to influence the pharmacokinetic results found experiment ally and is therefore a significant variable in its own right.