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Bupivacaine, but not lidocaine, may cause severe cardiac dysrhythmias in case of accidental intravascular injection. In an attempt to discriminate between a pharmacokinetic and a pharmacodynamic (or both) origin to these differences, we used an isolated rabbit heart model with constant coronary inflow to compare the myocardial uptake and disposition kinetics of lidocaine and bupivacaine. Drug concentration in the outflow perfusate was assayed and surface electrocardiogram was recorded. Drug uptake and disposition kinetics were modeled with a two-compartment open model. An Emax model was used to describe the increase in QRS duration in relation with drug concentration in the central compartment. Lidocaine and bupivacaine exhibited similar myocardial pharmacokinetics (i.e., a rapid decrease in the outflow concentration upon drug administration discontinuation). Bupivacaine-induced maximum increase in QRS duration (Emax) was 15 times superior to lidocaine Emax. The steady-state perfusate concentration producing half Emax was the same for both drugs. We conclude that bupivacaine-induced QRS widening decreases almost at the same rate as does lidocaine-induced QRS widening when drug administration is terminated. Therefore, the different cardiac effects of lidocaine and bupivacaine are not due to differences in myocardial uptake and disposition kinetics.