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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

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.

Keywords

Anticancer Drug Anticancer Activity Apparent Volume Crossover Design Weak Base 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Baguley BC, Denny WA, Atwell GJ, Finlay GJ, Rewcastle GW, Twigden SJ, Wilson WR (1984) Synthesis, antitumor activity and DNA binding properties of a new derivative of amsacrine; N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino)-phenylamino]-4-acridinecarboxamide. Cancer Res 44: 3245–3251Google Scholar
  2. 2.
    Bodey GP, Jacquillat C (1983) In: “Amascrine: Current perspectives and clinical results with a new anti-cancer agent”. Communications Media for Education, New JerseyGoogle Scholar
  3. 3.
    Bukowski RM, Legha SS, Saiki J, Eyre HJ, O'Bryan RO (1982) Phase II trial of m-AMSA in hepatocellular carcinoma: A Southwest Oncology Group Study. Cancer Treat Rep 66: 1651–1652Google Scholar
  4. 4.
    Cain BF, Atwell GJ (1974) The experimental antitumor properties of three congeners of the acridylmethanesulphonanilide (AMSA) series. Eur J Cancer 10: 539–549Google Scholar
  5. 5.
    Cysyk RLD, Shoemaker D, Adamson RH (1977) The pharmacologic disposition of 4′-(9-acridinylamino)methanesulfon-m-anisidide in mice and rats. Drug Metab Dispos 6: 579–590Google Scholar
  6. 6.
    Drelichman A, Decker DA, Al-Sarraf M, Dhabuwala CO (1982) m-AMSA in disseminated prostatic carcinoma: A phase II study. Cancer Treat Rep 66: 1993–1994Google Scholar
  7. 7.
    Gibaldi M, Perrier D (1982) Noncompartment analysis based on statistical moment theory In: Pharmacokinetics. Dekker, New YorkGoogle Scholar
  8. 8.
    Guentert TW, Jin-Ding H, Oie S (1982) Disposition of quinidine in the rabbit. J Pharm Sci 71: 812–815Google Scholar
  9. 9.
    Hiura M, Nakagawa S, Kawashima M, Kaneniwa N (1984) Effect of lipid solubility on hepatic first-pass metabolism of barbiturates in rabbits. Int J Pharm 20: 73–85Google Scholar
  10. 10.
    Jurlina JL, Paxton JW (1983) A high-performance liquid chromatographic method for the determination of 4′(acridinylamino)methanesulfon-m-anisidide (AMSA) in plasma. J Chromatogr 276:367–374Google Scholar
  11. 11.
    Jurlina JL, Paxton JW (1985) A high-performance liquid chromatographic assay for plasma concentrations of N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino)phenylamino]-4-acridinecarboxamide (CI-921, NSC 343499). J Chromatogr 342: 431–435Google Scholar
  12. 12.
    Jurlina JL, Varcoe AR, Paxton JW (1985) Pharmacokinetics of amsacrine in patients receiving combined chemotherapy for treatment of acute myelogenous leukemia. Cancer Chemother Pharmacol 14: 21–25Google Scholar
  13. 13.
    Legha SS, Keating MJ, McCredie KB, Bodey GP, Freireich EJ (1982) Evaluation of AMSA in previously treated patients with acute leukemia. Results of therapy in 109 adults. Blood 60: 484–490Google Scholar
  14. 14.
    Paxton JW, Jurlina JL (1985) Elimination kinetics of amsacrine in the rabbit. Evidence of nonlinearity. Pharmacology 31: 50–56Google Scholar
  15. 15.
    Rowland M, Tozer TN (1980) Clearance and renal exretion. In: Clinical pharmacokinetics: concepts and applications. Lea and Febiger, PhiladelphiaGoogle Scholar
  16. 16.
    Shoemaker DD, Cysyk RL, Gormley PE, De Souza JSV, Malspeis L (1984) Metabolism of 4′-(9-acridinylamino)methansulfon-m-anisidide by rat liver microsomes. Cancer Res 44: 1939–1946Google Scholar
  17. 17.
    Tozer TN, Gambertoglio JG, Furst DE, Avery DS, Holford NHG (1983) Volume shifts and protein binding estimates using equilibrium dialysis: Application to prednisolone binding in humans. J Pharm Sci 72: 1442–1448Google Scholar
  18. 18.
    Warrel RP, Strauss DJ, Young CW (1980) Phase II trial of 4′-(9-acridinylamino)methansulfon-m-anisidide in the treatment of advanced non-Hodgkin's lymphoma. Cancer Treat Rep 64: 1157–1158Google Scholar

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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