KINETICS OF BUPIVACAINE AFTER NICORANDIL TREATMENT IN MICE

Previous studies have reported interactions between potassium-channel agonists and bupivacaine. This study was designed to document possible changes in the pharmacokinetic behaviour of bupivacaine and its main metabolite, N-desbutylbupivacaine, in mice after a single 1 mg kg(-1) intraperitoneal injection of nicorandil. The kinetic variables of bupi vacaine were determined after a single 20 mg kg(-1) intraperitoneal do se of bupivacaine in controls (group 1) and in nicorandil-treated mice (group 2). The maximal concentration in the serum (C-max 0.618 +/- 0. 051 vs 0.408 +/- 0.041 mu g mL(-1) for group 1 vs 2, P = 0.01) and the area under the concentration curve (AUC 1.039 +/- 0.051 vs 0.758 +/- 0.072 mu g mL(-1) h for group 1 vs 2, P = 0.013) of bupivacaine were s ignificantly lower in nicorandil-treated mice, while CL (0.579 +/- 0.0 25 vs 0.815 +/- 0.079 for group 1 vs 2, P = 0.022) and V-d (0.506 +/- 0.054 vs 0.981 +/- 0.117 for group 1 vs 2, P = 0.1006) were increased in nicorandil-treated animals. The ratio of AUC for N-desbutylbupivaca ine to AUC for bupivacaine, which may partially indicate the rate of m etabolism, was higher in the presence of nicorandil (1.142 +/- 0.017 c ompared with 0.877 +/- 0.013, P = 0.0001). Our data may indicate an in creased metabolism of bupivacaine in nicorandil-treated mice. These re sults do not explain the previously reported enhanced anaesthetic acti vity of bupivacaine in the presence of nicorandil but may participate, at least in part, in the relative protective effect of nicorandil aga inst the previously reported bupivacaine-induced toxicity.