Dose-dependent pharmacokinetics of N-5-dimethyl-9-[(2-methoxy-4-methylsulphonylamino)phenylamino]- 4-acridinecarboxamide (CI-921) in rabbits.

N-5-dimethyl-9-[(2-methoxy-4-methylsulphonylamino)phenylamino]-4- acridinecarboxamide (CI-921), which is an analogue of amsacrine, has entered phase I clinical trials as an antitumour drug. The plasma pharmacokinetics of CI-921 has been studied in six rabbits after short i.v. infusions of 6.35, 12.7 and 25.4 mumol/kg. Total plasma concentrations of CI-921 were determined by a high-performance liquid chromatography method for up to 12 h post infusion. Comparison of pharmacokinetic parameters for each rabbit by within-subject analysis of variance indicated that with a four-fold increase in the dose from 6.35 to 25.4 mumol/kg there was a 44% increase in the area under the concentration-time curve normalised to dose (P less than 0.001) and a 43% increase in the elimination half-life (P less than 0.005), and a 30% decrease in the total plasma clearance (P less than 0.001). Dose had no effect on the end of infusion concentration normalised to dose, or on the steady-state volume of distribution. These results indicate that CI-921 experiences dose-dependent elimination kinetics in the rabbit.