Elimination Kinetics of Amsacrine in the Rabbit: Evidence of Nonlinearity

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Abstract
Plasma amsacrine [an antitumor drug] kinetics were studied in rabbits after different doses (2.5-10 mg/kg) infused over 35 min. Amsacrine concentrations were measured by HPLC [high-performance liquid chromatography] and plasma protein binding by equilibrium dialysis. All elimination curves were best fitted by a bi-exponential expression with a mean t1/2.alpha. [.alpha.-phase half-life] of 0.56 h and t1/2.beta. of 2.47 h. At doses > 5 mg/kg, there appeared to be an overproportional increase in the area under the curve, suggesting nonlinear 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 .mu.mol/l. The rabbit is evidently an acceptable model for further studies of the pharmacokinetics of amsacrine and its analogs, at doses .ltoreq. 5 mg/kg.