Myocardial uptake of bupivacaine: II. Pharmacokinetics and pharmacodynamics of bupivacaine enantiomers in the isolated perfused rabbit heart.
The enantiomers of a racemic drug generally differ in their pharmacokinetic and/or pharmacodynamic properties. Because bupivacaine is a mixture of two optical isomers known to exert different toxic properties on isolated nerve preparations, we decided to use an isolated rabbit heart model with constant coronary inflow to compare the myocardial uptake kinetics of the R(+)-, S(-)-enantiomers and the racemic mixture of bupivacaine. The increase in QRS duration was also measured, and the inflow concentration-effect relationship was analyzed for the three drugs. The racemic and the two enantiomers of bupivacaine exhibited similar myocardial pharmacokinetics with a two-compartment profile for all hearts except one. All drugs showed a rapid decrease in the outflow concentration when drug administration was discontinued. The tissue/perfusate concentration ratio at steady state was similar for the three drugs. QRS widening, as well as the occurrence of severe arrhythmias, was much less pronounced in the hearts receiving the S(-) isomer than in the hearts receiving the R(+) isomer or the racemic mixture. Despite the occurrence of arrhythmias, QRS widening was adequately modelled with an Emax model. C50, the inflow perfusate concentration producing half Emax (maximal theoretical increase in QRS duration) was the same for all three drugs. The authors conclude that the S(-)-bupivacaine exerts less detrimental effects on the isolated heart of the rabbit perfused at a constant coronary flow with protein-free buffer.
Mazoit
J X
JX
Laboratoire d'Anesthésie-Réanimation, Université Paris-Sud, Le Kremlin-Bicêtre, France.
Boïco
O
O
Samii
K
K
D000818:Animals; D001835:Body Weight; D002045:Bupivacaine / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009929:Organ Size; D010477:Perfusion; D011817:Rabbits; D013237:Stereoisomerism
D002045:Bupivacaine