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 bupivacaine were determined after a single 20 mg kg-1 intraperitoneal dose of bupivacaine in controls (group 1) and in nicorandil-treated mice (group 2). The maximal concentration in the serum (Cmax 0.618 +/- 0.051 vs 0.408 +/- 0.041 microgram 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 microgram mL-1 h for group 1 vs 2, P = 0.013) of bupivacaine were significantly lower in nicorandil-treated mice, while CL (0.579 +/- 0.025 vs 0.815 +/- 0.079 for group 1 vs 2, P = 0.022) and Vd (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-desbutylbupivacaine to AUC for bupivacaine, which may partially indicate the rate of metabolism, was higher in the presence of nicorandil (1.142 +/- 0.017 compared with 0.877 +/- 0.013, P = 0.0001). Our data may indicate an increased metabolism of bupivacaine in nicorandil-treated mice. These results do not explain the previously reported enhanced anaesthetic activity of bupivacaine in the presence of nicorandil, but may participate, at least in part, in the relative protective effect of nicorandil against the previously reported bupivacaine-induced toxicity.