Prilocaine elimination by isolated perfused rat lung and liver

Abstract

Prilocaine is assumed to undergo significant elimination by extrahepatic organs and to differ in this respect from other commonly used local anaesthetics. In order to clarify whether the lung may play an important role as a site of elimination of prilocaine, the kinetic parameters were studied in isolated perfused rat lungs and were compared to those of isolated livers. Furthermore, the structurally related compounds bupivacaine and mepivacaine were also investigated in this system. Prilocaine was dispersed into a relatively large apparent distribution volume in perfused rat lung (139 ml versus 97 ml in controls). In single-pass perfused lungs the observed maximum of concentration was decreased by about 60% compared to controls. The mean residence time was prolonged by about 40%. These observations suggest that prilocaine is substantially retained by rat lung and that this effect occurs particularly during first-pass.

However, the ability of rat lung to degrade prilocaine was relatively low. The clearance values were about 0.3 ml/min equal to about 20% of the hepatic capacity calculated per g of tissue. Thus it must be assumed that prilocaine is only transiently retained by the lung and will gain systemic availability later on. In rat lungs the kinetics of prilocaine elimination were not substantially different from those of bupivacaine and mepivacaine (16 and 12%). These observations do not support the assumption that especially prilocaine undergoes extrahepatic elimination.

For low (2 μg/ml) and intermediate (10 μg/ml) drug concentrations isolated rat liver exhibited clearance values close to the perfusion flow rate. Accordingly, prilocaine was removed from the perfusion medium of isolated livers already during first-pass. At very high concentrations of 100 μg/ml, the clearance dropped to about half of the control values. Thus under these conditions approximately half of the dose escaped first-pass extraction which is probably caused by saturated metabolic clearance. Such an effect was not observed for bupivacaine and mepivacaine.