Pharmacokinetics of Bupivacaine during Postoperative Epidural Infusion

Abstract

Background: Changing plasma protein concentrations may affect the protein binding and pharmacokinetics of drugs in the postoperative period. This study examined the effect of postop- erative increases (in response to surgery) in plasma ? 1-acid- glycoprotein (AAG) concentrations on the plasma concentra- tions of the enantiomers of bupivacaine during continuous epidural infusion of racemic bupivacaine for postoperative pain relief. Methods: Six patients scheduled for total hip surgery with combined epidural and general anesthesia received a bolus dose of bupivacaine (65 mg) followed by constant-rate (8 ml/h) epidural infusion of 2.5 mg/ml bupivacaine for 48 h. Total and unbound plasma concentrations of the enantiomers of bupiva- caine and plasma AAG concentrations during the 48-h epidural infusion were determined. Results: Total plasma concentrations of the enantiomers of bupivacaine increased steadily during the infusion (P < 0.0001), whereas unbound concentrations did not change after 12h(P>0.1). Total plasma concentrations of S(?)-bupivacaine were higher than those of R(?)-bupivacaine (P < 0.02), whereas unbound concentrations of S(?)-bupivacaine were lower than those of R(?)-bupivacaine (P < 0.002). AAG concen- trations initially decreased, but thereafter increased steadily (P < 0.0001). Consequently, free fractions of the enantiomers initially increased and then decreased with time (P ? 0.0002). Free fractions of S(?)-bupivacaine were smaller than those of R(?)-bupivacaine (P ? 0.0003). Conclusions: The study confirmed that the pharmacokinetics of bupivacaine are enantioselective. During postoperative epi- dural infusion, changing plasma AAG concentrations affect the protein binding of both enantiomers of bupivacaine. Conse- quently, total plasma concentrations of the enantiomers in- crease with time, whereas unbound concentrations reach a plateau. CONT