Elimination kinetics of amsacrine in the rabbit: evidence of nonlinearity.

Plasma amsacrine kinetics have been studied in rabbits after different doses (2.5-10 mg/kg) infused over 35 min. Amsacrine concentrations were measured by HPLC and plasma protein binding by equilibrium dialysis. All elimination curves were best fitted by a bi-exponential expression with a mean t 1/2 alpha of 0.56 h and t 1/2 beta of 2.47 h. At doses greater than 5 mg/kg, there appeared to be an overproportional increase in the area under the curve, suggesting non-linear kinetics. Comparison of pharmacokinetic parameters indicated a significant decrease in plasma Cl after the 10-mg/kg dose compared to the 5- and 2.5-mg/kg dose. Amsacrine was highly bound by plasma (96.8%) over the concentration range 1-100 mumol/l. It is concluded that the rabbit is an acceptable model for further studies of the pharmacokinetics of amsacrine and its analogues at doses less than or equal to 5 mg/kg.