Chemotherapy pp 119-127 | Cite as

Pharmacokinetics and Metabolism of Anticancer Drugs

  • Ti Li Loo


The design of cancer chemotherapeutic agents would already have evolved from empiricism to rationalism if a unique structural feature exists that specifically confers anticancer activity on a chemical substance. In reality, the structures of anticancer drugs vary widely; this structural diversity dictates a similar diversity in the pharmacokinetics and metabolism of these drugs. Generally however, the pharmacological disposition and metabolism of a particular class of anticancer agents, the antimetabolites, closely mimic those of their natural counterparts, and a reasonable extrapolation can frequently be made.


Anticancer Drug Drug Metabolism Antitumor Agent Nitrogen Mustard Anthracycline Antibiotic 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    B. Clarkson, A. O’Connor, L. Winston, and D. Hutchinson: The physiologic disposition of 5-fluorouracil and 5-fluoro-2′-deoxyuridine in man. Clin. Pharmac. Therap., 5, 581 (1964).Google Scholar
  2. 2.
    L. S. Schanker and J. J. Jeffrey: Active transport of foreign pyrimidines across the intestinal epithelium. Nature, 190, 727 (1961).PubMedCrossRefGoogle Scholar
  3. 3.
    T. L. Loo, J. K. Luce, M. P. Sullivan, and E. Frei, III: Clinical pharmacologic observations on 6-mercaptopurine and 6-methylthiopurine ribonucleoside. Clin. Pharmac. Therap., 9, 180 (1968).Google Scholar
  4. 4.
    I. D. Goldman, N. S. Lichtenstein, and V. T. Oliverio: Carrier-mediated transport of the folic acid analogue, methotrexate, in the L1210 leukemic cells. J. Biol. Chem., 243, 5007 (1968).PubMedGoogle Scholar
  5. 5.
    R. M. Lyons and G. J. Goldenberg: Active transport of nitrogen mustard and choline by normal and leukemic human lymphoid cells. Cancer Res., 32, 1679 (1972).PubMedGoogle Scholar
  6. 6.
    D. P. Rall, R. E. Rieselbach, V. T. Oliverio, and E. Morse: Pharmacology of folic acid antagonists as related to brain and cerebrospinal fluid. Cancer Chemoth. Rep., 16, 187 (1962).Google Scholar
  7. 7.
    T. L. Loo, J. K. Luce, J. H. Jardine, and E. Frei, III: Pharmacologic studies of the antitumor agent 5-(dimethyltriazeno)-imidazole-4-carboxamide. Cancer Res., 28 2448 (1968).PubMedGoogle Scholar
  8. 8.
    T. L. Loo, K. Lu, and J. A. Gottlieb: Disposition and metabolism of thiopurines. II. Arabinosyl-6-mercaptopurine and ribosyl-6-mercaptopurine. Drug Met. Disp., 1, 645 (1973).Google Scholar
  9. 9.
    R. S. Bourke, C. R. West, G. Chheda, and D. B. Tower: Kinetics of entry and distribution of 5-fluorouracil in cerebrospinal fluid and brain following intravenous injection in a primate. Cancer Res., 33, 1735 (1973).PubMedGoogle Scholar
  10. 10.
    K. Lu, T. L. Loo, J. A. Benvenuto, R. S. Benjamin, M. Valdivieso, and E. J Freireich: Pharmacologic disposition and metabolism of ftorafur. Pharmacologist, 17, 1975).Google Scholar
  11. 11.
    D. H. W. Ho, B. Thetford, C. J. K. Carter, and E. Frei, III: Clinical pharmacologic studies of L-asparaginase. Clin. Pharmacol. Therap., 11, 408 (1970).Google Scholar
  12. 12.
    T. L. Loo, R. L. Dion, R. L. Dixon, and D. P. Rall: The antitumor agent, l,3-bis(2-chloroethyl)-l-nitrosourea. J. Pharm. Sci., 55, 492 (1966).CrossRefGoogle Scholar
  13. 13.
    M. D. Walker: Physiologic barriers to pharmacologic efficacy. Proc. 5th Int. Congr. Pharmac, 3, 354 (1973).Google Scholar
  14. 14.
    D. G. Johns, D. Farquhar, and T. L. Loo: Physiologic disposition of the di-amyl ester of 3′,5′-3H-methotrexate in the dog. Pharmacologist, 16, 231 (1974).Google Scholar
  15. 15.
    K. B. Bischoff, R. L. Dedrick, D. S. Zaharko, and J. A. Longstreth: Methotrexate Pharmacokinetics. J. Pharm. Sci., 60, 1128 (1971).PubMedCrossRefGoogle Scholar
  16. 16.
    R. L. Dedrick, D. D. Forrester, and D. H. W. Ho: In vitro in vivo correlation of drug metabolism — Deamination of 1-ß-D-ara-binofuranosylcytosine. Biochem. Pharmacol., 21, 1 (1972).PubMedCrossRefGoogle Scholar
  17. 17.
    T. L. Loo, D. H. W. Ho, G. P. Bodey, and E. J Freireich: Pharmacological and clinical studies of some nucleoside analogues. Ann. N. Y. Acad. Sci. (1975).Google Scholar
  18. 18.
    E. S. Henderson, R. H. Adamson, and V. T. Oliverio: The metabolic fate of tritiated methotrexate. II. Absorption and excretion in man. Cancer Res., 25, 1018 (1965).PubMedGoogle Scholar
  19. 19.
    T. L. Loo and S. E. Sugarek: Unpublished work.Google Scholar
  20. 20.
    D. W. Donigian and R. J. Owellen: Interaction of vinblastine, vincristine, and colchicine with serum proteins. Biochem. Pharmac., 22, 2113 (1973).CrossRefGoogle Scholar
  21. 21.
    R. S. Benjamin, P. H. Wiernik, and N. R. Bachur: Adriamycin chemotherapy — efficacy, safety, and pharmacologic basis of an intermittent single high-dose schedule. Cancer, 33, 19 (1974).PubMedCrossRefGoogle Scholar
  22. 22.
    V. T. Oliverio and J. D. Davidson: The physiological disposition of dichloromethotrexate — 36C1 in animals. J. Pharmac. Exp. Ther., 137, 76 (1962).Google Scholar
  23. 23.
    N. B. Kuemmerle: Hepatobiliary excretion of 5-(3,3-dimethyl-l-triazeno)-imidazole-4-carboxamide (DIC) in the rat. M.S. Thesis, The Univ. of TX System Health Sci. Ctr. at Houston Grad. Sch. of Biomed. Sci., 1975.Google Scholar
  24. 24.
    R. J. Owellen and D. W. Donigian: [3H] Vincristine. Preparation and preliminary pharmacology. J. Med. Chem., 15, 894 (1972).PubMedCrossRefGoogle Scholar
  25. 25.
    D. R. Brand: Hepatobiliary excretion of Baker’s folate antagonist in the rat. M.S. Thesis, The Univ. of TX System Health Sci. Ctr. at Houston Grad. Sch. of Biomed. Sci., 1975.Google Scholar
  26. 26.
    J. L. Skibba, D. D. Beal, G. Ramirez, and G. T. Bryan: N-demethylation of the antineoplastic agent 4(5)-(3,3-dimethyl-l-triazeno)imidazole-5(4)-carboxamide by rats and man. Cancer Res., 30, 147 (1970).PubMedGoogle Scholar
  27. 27.
    D. L. Hill, W. R. Laster, Jr., M. C. Kirk, S. El Dareer, and R. F. Struck: Metabolism of iphosphamide [2-(2-chloroethylamino)-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide] and production of a toxic iphosphamide metabolite. Cancer Res., 33, 1016 (1973).PubMedGoogle Scholar
  28. 28.
    H. E. May, R. Boose, and D. J. Reed: Hydroxylation of the carcinostatic 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) by rat liver microsomes. Biochem. Biophys. Res. Comm., 57, 426 (1974).PubMedCrossRefGoogle Scholar
  29. 29.
    D. L. Hill, M. C. Kirk, and R. F. Struck: Microsomal metabolism of nitrosoureas. Cancer Res., 35, 296 (1975).PubMedGoogle Scholar
  30. 30.
    N. R. Bachur and M. Gee: Daunorubicin metabolism by rat tissue preparations. J. Pharmac. Exp. Ther., 177, 567 (1971).Google Scholar
  31. 31.
    M. A. Asbell, E. Schwartzbach, F. J. Bullock, and D. W. Yesair: Daunomycin and adriamycin metabolism via reductive glucosidic cleavage. J. Pharmac. Exp. Ther., 182, 63 (1972).Google Scholar
  32. 32.
    T. L. Loo and J. Friedman: Unpublished work.Google Scholar
  33. 33.
    R. Kato, A. Takanaka, A. Takahashi, and K. Onoda: Drug metabolism in tumor-bearing rats. Jap. J. Pharmac, 18, 245 (1968), and subsequent papers.CrossRefGoogle Scholar
  34. 34.
    R. Rosso, M. G. Donelli, G. Franchi, and S. Garattini: Impairment of drug metabolism in tumor-bearing animals. Europ. J. Cancer, 7, 565 (1971).Google Scholar
  35. 35.
    G. E. Housholder and T. L. Loo: Disposition of 5-(3,3-dimethyl-l-triazeno)imidazole-4-carboxamide, a new antitumor agent. J. Pharmac. Exp. Ther., 179, 386 (1971).Google Scholar
  36. 36.
    G. J. Goldenberg: Drug-induced stimulation of nitrogen mustard and choline transport and other systems in L5178Y lympho-blasts in vitro. Cancer Res., 34 2511 (1974).PubMedGoogle Scholar
  37. 37.
    A. Nahas and R. L. Capizzi: Effect of in vivo treatment with L-asparaginase on the in vivo uptake and retention of some anti-leukemic agents. Cancer Res., 34, 2689 (1974).PubMedGoogle Scholar
  38. 38.
    R. F. Zager, S. A. Frisby, and V. T. Oliverio: The effects of antibiotics and cancer chemotherapeutic agents on the cellular transport and antitumor activity of methotrexate in L1210 murine leukemia. Cancer Res., 33, 1670 (1973).PubMedGoogle Scholar
  39. 39.
    D. G. Liegler, E. S. Henderson, M. A. Hahn, and V. T. Oliverio: The effect of organic acids on renal clearance of methotrexate in man. Clin. Pharmac. Ther., 10, 849 (1969).Google Scholar
  40. 40.
    F. Pannuti, A. Ligabue, and F. Trasarti: Interferenza farmacologica in oncologia: Variazioni della cinetica della 6-mercap-topurina (6-MP) in animali pretrattati con methotrexate (MTX). Boll. Soc. Ital. Biol. Sper., 48, 574 (1972).Google Scholar
  41. 41.
    R. G. Tardiff and K. P. DuBois: Inhibition of hepatic microsomal enzymes by alkylating agents. Arch. Int. Pharmacodyn., 127, 445 (1969).Google Scholar
  42. 42.
    M. G. Donelli, G. Franchi, and R. Rosso: The effect of cytotoxic agents on drug metabolism. Europ. J. Cancer, 6, 125 (1970).Google Scholar
  43. 43.
    P. Klubes and I. Cerna: Effect of 5-fluorouracil on drug-metabolizing enzymes in the rat. Cancer Res., 34, 927 (1974).PubMedGoogle Scholar
  44. 44.
    P. J. Creaven, L. M. Allen, and C. P. Williams: The interaction of the antineoplastic drug thalicarpine with aniline hydroxylase and microsomal cytochrome of rat liver. Xenobiotica, 4, 255 (1974).PubMedCrossRefGoogle Scholar
  45. 45.
    T. K. Basu and D. C. Williams: Effects of methotrexate and phenobarbital on the hepatic microsomal drug-metabolizing enzymes in normal rats. Chemoth., 21, 33 (1975).CrossRefGoogle Scholar
  46. 46.
    D. Farquhar and T. L. Loo: BCG-induced impairment of drug-metabolizing enzyme activities of the rat liver. Pharmacologist, 16, 239 (1974).Google Scholar

Copyright information

© Plenum Press, New York 1976

Authors and Affiliations

  • Ti Li Loo
    • 1
  1. 1.M.D. Anderson Hospital and Tumor InstituteThe University of Texas System Cancer CenterHoustonUSA

Personalised recommendations