Summary
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.
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The work described in this paper was supported by a grant from the Medical Research Council of New Zealand. It was reported on at the 18th Annual Meeting of the Australasian Society of Clinical and Experimental Pharmacologists, Melbourne, Australia, December 1984
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Paxton, J.W., Jurlina, J.L. 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. Cancer Chemother. Pharmacol. 16, 253–256 (1986). https://doi.org/10.1007/BF00293987
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DOI: https://doi.org/10.1007/BF00293987