EFFECTS OF CALCIUM-ANTAGONISTS ON BINDING OF LOCAL-ANESTHETICS TO PLASMA-PROTEINS AND ERYTHROCYTES IN MICE

This study was designed to document possible changes in the binding of bupivacaine (BV), lidocaine (LC) and their main metabolites desbutylb upivacaine (PPX) and monoethylglycinexylydide (MEGX), respectively, to plasma proteins and erythrocytes in mice after acute treatment with t he calcium antagonists diltiazem (DZ), nicardipine (NP) and verapamil (VP). A significant plasma protein binding of BV, LC and PPX was measu red, whereas no binding could be detected for MEGX. The binding of BV was not modified by DZ, NP and VP, however, the total plasma level was increased in the presence of VP. For PPX a significant increase in to tal and free plasma levels and a decrease in protein binding were demo nstrated after DZ and VP treatment. Concerning LC, a significant incre ase in total and free plasma levels was documented for DZ, NP and VP s uggesting an inhibition of the metabolism of LC by the calcium antagon ists. An increased penetration of LC into erythrocytes was also demons trated which is consistent with the calcium antagonist-induced increas e in LC free plasma levels. These effects may contribute in part to th e previously observed increase in toxicity of BV by calcium antagonist s, but are not likely to be the sole mechanism.