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Disposition of Amsacrine and Its Analogue 9-({;2-Methoxy-4-[(methylsulfonyl)-amino]phenyl}amino)-N,5-dimethyl-4-acridinecarboxamide (CI-921) in Plasma, Liver, and Lewis Lung Tumors in Mice¹

Cancer Research Laboratory [P. K., J. L. J., B. C. B.] and Department of Pharmacology and Clinical Pharmacology [J. W. P., P. C. E., D. Y., I. G. C. R.], University of Auckland Medical School, Private Bag, Auckland, New Zealand

9-({2-Methoxy-4-[(methylsulfonyl)amino]phenyl}amino)-N,5-dimethyl-4-acridinecarboxamide (CI-921), an analogue of the clinical antileukemia drug amsacrine with improved solid tumor activity in mice, is currently being evaluated in patients. In order to determine whether CI-921 possesses any advantages over amsacrine in terms of tissue delivery, the pharmacokinetics of amsacrine and CI-921 were determined following i.v. injection in male B6D2F₁ mice. Plasma kinetics in normal mice were measured following administration of 14.4, 28.9, and 57.7 µmol/kg. The kinetics in s.c. Lewis lung tumors, and in plasma and livers of normal and tumor-bearing mice were measured following administration of 57.7 µmol/kg. CI-921 and amsacrine were quantitated by high-performance liquid chromatography after extraction from plasma and from liver and tumor homogenates. In experiments with appropriate ³H-labeled compounds, both total and covalently bound radioactivity (determined after precipitation and washing with acetonitrile) were measured in plasma and in liver homogenates. Over this dose range, nonlinear kinetics were observed in plasma for unchanged CI-921 and amsacrine, and a reasonable fit was obtained with Michaelis-Menten kinetics to a one-compartment model for CI-921 (K_m 3.7 µmol/liter; V_max 18 µmol/h/kg; V_ss 3.3 liter/kg) and a two-compartment model for amsacrine (K_m 3.6 µmol/liter; V_max 76 µmol/h/kg; V_ss 4.8 liter/kg). The area under the concentration-time curve (AUC) for plasma following a dose of 57.7 µmol/kg was 31 µmol·h/liter for CI-921 and 6.3 µmol·h/liter for amsacrine. However, equilibrium dialysis measurements indicated high plasma protein binding with free drug fractions for CI-921 and amsacrine of 0.63 and 6.7%, respectively. In the liver, unchanged drug concentrations and total radioactivity for both compounds were approximately 10-fold those in plasma, and the tissue half-life of CI-921 was approximately 4-fold longer for CI-921 than for amsacrine. Plasma and liver kinetics in mice with s.c. Lewis lung tumors were similar to those in normal mice. Tumor half-lives of unchanged CI-921 and amsacrine were 3.9 and 2.7 h, respectively, considerably longer than those for plasma (1.2 and 0.30 h respectively) or liver (1.2 and 0.28 h, respectively). Tumor AUC values for CI-921 and amsacrine were 68 and 37 µmol·h/liter, respectively, as compared to the calculated AUC values for free drug in plasma of 0.19 and 0.42 µmol·h/liter, respectively. It is concluded that the uptake into tumors from the plasma free drug fraction is more efficient for CI-921 than for amsacrine.

¹ Supported by the Auckland Division of the Cancer Society of New Zealand, the Medical Research Council of New Zealand and a Warner-Lambert Fellowship.

² To whom requests for reprints should be addressed, at Cancer Research Laboratory, University of Auckland Medical School, Private Bag, Auckland, New Zealand.

Received 5/ 8/89. Revised 9/11/89. Accepted 10/10/89.