Pharmacokinetics of bupivacaine during postoperative epidural infusion: enantioselectivity and role of protein binding.
BACKGROUND
Changing plasma protein concentrations may affect the protein binding and pharmacokinetics of drugs in the postoperative period. This study examined the effect of postoperative increases (in response to surgery) in plasma alpha1-acid-glycoprotein (AAG) concentrations on the plasma concentrations 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 bupivacaine 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 12 h (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 concentrations 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 epidural infusion, changing plasma AAG concentrations affect the protein binding of both enantiomers of bupivacaine. Consequently, total plasma concentrations of the enantiomers increase with time, whereas unbound concentrations reach a plateau.
Veering
Bernadette Th
BT
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. B.Th.Veering@lumc.nl
Burm
Anton G L
AG
Feyen
Hilde-Marieken
HM
Olieman
Wim
W
M  Souverijn
John H
JH
Van Kleef
Jack W
JW
D000368:Aged; D000465:Algorithms; D015360:Analgesia, Epidural; D000779:Anesthetics, Local / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002045:Bupivacaine / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009961:Orosomucoid / Q000378:metabolism; D010147:Pain Measurement; D010149:Postoperative Pain / Q000188:drug therapy*; D011485:Protein Binding; D013237:Stereoisomerism
D000779:Anesthetics, Local; D009961:Orosomucoid; D002045:Bupivacaine