Systemic and regional pharmacokinetics of levobupivacaine and bupivacaine enantiomers in sheep.
Commercially available bupivacaine is an equimolar mixture of R(+)- and S(-)-bupivacaine. S(-)-bupivacaine (levobupivacaine) is the subject of current clinical evaluation. We conducted partial cross-over systemic and regional pharmacokinetic studies of i.v. bupivacaine (12.5-200 mg) and levobupivacaine (6.25-200 mg) in ewes. Enantiospecific analysis of blood drug concentration-time data and of regional myocardial and brain drug mass balance data indicated that (a) there was a higher mean total body clearance of R(+)-bupivacaine than of S(-)-bupivacaine (as previously reported); (b) there were no differences in the systemic pharmacokinetics of S(-)-bupivacaine whether administered alone or as a component of bupivacaine; (c) there was no evidence of dose-dependent pharmacokinetics with either enantiomer; (d) for both enantiomers, mean calculated myocardial tissue concentrations of 1%-4% dose occurred between 3 and 5 min. Mean brain concentrations of 0.2%-1% dose occurred between 2 and 4 min after the administration of bupivacaine but between 4 and 5 min after the administration of levobupivacaine. There was no evidence that systemic toxicity induced by these local anesthetics significantly modified their pharmacokinetics, and there was no evidence of an enantiomer-enantiomer pharmacokinetic interaction for bupivacaine.


CONCLUSIONS
Levobupivacaine comprises 50% of commercially available bupivacaine and is being considered for use in its own right. As a part of its preclinical evaluation, this study considered whether levobupivacaine behaved kinetically in the body in the same way as when administered as a component of bupivacaine.
Mather
L E
LE
Department of Anaesthesia and Pain Management, The University of Sydney at Royal North Shore Hospital, St. Leonards, New South Wales, Australia.
Huang
Y F
YF
Veering
B
B
Pryor
M E
ME
D000779:Anesthetics, Local / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D001158:Arteries; D001921:Brain / Q000378:metabolism; D002045:Bupivacaine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D009206:Myocardium / Q000378:metabolism; D012756:Sheep; D013237:Stereoisomerism; D013997:Time Factors; D014018:Tissue Distribution; D014680:Veins
D000779:Anesthetics, Local; D002045:Bupivacaine