Bupivacaine kinetic changes induced by diltiazem in mice

This study was designed to document possible changes in bupivacaine and its main metabolite, des-butyl-bupivacaine (PPX) kinetics in mice after a single 5 mg/kg injection of diltiazem. After a single 20 mg/kg i.p. dose of bupivacaine, kinetic parameters of bupivacaine were not statistically different but the ratio AUC PPX/AUC bupivacaine was significantly lower when bupivacaine was associated with diltiazem: thus, it may indicate an influence of diltiazem on bupivacaine metabolism i.e. an inhibition. Diltiazem also seems to increase the free fraction of bupivacaine and thus to decrease the percentage of protein binding. These effects may contribute to the enhanced toxicity previously observed.