Cancer Chemotherapy and Pharmacology

, Volume 16, Issue 3, pp 253–256 | Cite as

Comparison of the pharmacokinetics and protein binding of the anticancer drug, amsacrine and a new analogue, N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino)phenyl-amino]-4-acridinecarboxamide in rabbits

  • James W. Paxton
  • Jeffrey L. Jurlina
Original Articles Amsacrine


Amsacrine (NSC 249992) is a new anticancer drug which, although effective for the treatment of various disseminated tumors, has shown disappointing activity against most solid tumors. A new analogue, N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino)phenylamino]-4-acridine-carboxamide (CI-921, NSC 343499) has been identified, which might offer a broader clinical antitumor spectrum. This analogue is more lipophilic (0.5 log p units) and is also a considerable weaker base (pKa 6.40) than amsacrine (pKa 7.43). This study compared the pharmacokinetics of total and unbound amsacrine and CI-921 in plasma after equimolar dose infusions (12.7 μmol/kg) in a balanced crossover design in six rabbits. Drug concentrations were determined by high-pressure liquid chromatography and the unbound fraction by equilibrium dialysis. Three fold higher total plasma concentrations were achieved with CI-921 than with amsacrine. However, the unbound fraction was significantly less for CI-921 (0.33%±0.04) than for amsacrine (2.78%±0.53). There was no significant difference between distribution and elimination half-life and mean residence time, but the apparent volume of distribution (means, 121 vs 45 l/kg) and clearance (means, 46.6 vs 16.3 l h-1 kg-1) of unbound CI-921 were threefold greater than the corresponding parameters for unbound amsacrine. We suggest that despite higher binding in plasma, the greater distribution or tissue uptake of CI-921 may be partly responsible for its greater anticancer activity in vivo.


Anticancer Drug Anticancer Activity Apparent Volume Crossover Design Weak Base 
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Copyright information

© Springer-Verlag 1986

Authors and Affiliations

  • James W. Paxton
    • 1
  • Jeffrey L. Jurlina
    • 2
  1. 1.Department of Pharmacology and Clinical PharmacologyUniversity of Auckland School of MedicineAucklandNew Zealand
  2. 2.Cancer Research LaboratoryUniversity of Auckland School of MedicineAucklandNew Zealand

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