Clinical Pharmacokinetics

, Volume 34, Issue 5, pp 347–358

Pharmacokinetics and Pharmacodynamics of Hydroxyurea

Review Article Drug Disposition

Abstract

Hydroxyurea is used in the treatment of various forms of cancer, sickle-cell anaemia and HIV infection. Oral absorption of the drug is virtually complete, the volume of distribution is equivalent to total body water and elimination is through both renal and nonrenal mechanisms. Nonrenal elimination of hydroxyurea is characterised by Michaelis-Menten kinetics.

Further studies are necessary to clarify several aspects of the pharmacokinetics and pharmacodynamics of hydroxyurea: the effect of age and disease state, concentration-effect relationship, the role of therapeutic drug monitoring, and the mechanisms of renal and nonrenal elimination. The recent development of improved assays for hydroxyurea should have benefits for future pharmacokinetic studies.

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References

  1. 1.
    Dresler WFC, Stein R. Uber den hydroxhylarnstoff. Justus Liebigs Ann Chem Pharm. 1869; 150: 242–52.CrossRefGoogle Scholar
  2. 2.
    Rosenthal F, Wislicki L, Kollek L. Uber die Beziehungen von schwersten Blutgiften zu Abbauprodukten des Eiweisses: ein Betrag zum Entstehungsmechanismus der perniziosen Anamie. Klin Wochenschr. 1928; 7: 972–7.CrossRefGoogle Scholar
  3. 3.
    Stearns B, Losee KA, Bernstein J. Hydroxyurea: a new type of potential antitumor agent. J Med Chem. 1963; 6: 201.PubMedCrossRefGoogle Scholar
  4. 4.
    Yarbro JW, Kennedy BJ, Barnum CP. Hydroxyurea inhibition of DNA synthesis in ascites tumor. Proc Natl Acad Sci U S A. 1965; 53: 1033–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Yarbro JW. Mechanism of action of hydroxyurea. Semin Oncol 1992; 19 (3 Suppl. 9): 1–10.PubMedGoogle Scholar
  6. 6.
    Krakoff IH, Brown NC, Reichard P. Inhibition of ribonucleoside diphosphate reductase by hydroxyurea. Cancer Res. 1968; 28: 1559–65.PubMedGoogle Scholar
  7. 7.
    Wright JA, Chan AK, Choy BK, et al. Regulation and drug resistance mechanisms of mammalian ribonucleotide reductase, and the significance to DNA sysnthesis. Biochem Cell Biol. 1990; 68(12): 1364–71.PubMedCrossRefGoogle Scholar
  8. 8.
    Stubbe J. Ribonucleotide reductases. Adv Enzymol Relat Areas Mol Biol. 1990; 63: 3494–19.Google Scholar
  9. 9.
    Lassmann G, Liermann B. ESR studies of structure and kinetics of radicals from hydroxyurea: an antitumor drug directed against ribonucleotide reductase. Free Radic Biol Med. 1989; 6(3): 241–4.PubMedCrossRefGoogle Scholar
  10. 10.
    Graslund A, Ehrenberg A, Thelander L. Characterization of the free radical of mammalian ribonucleotide reductase. J Biol Chem. 1982; 257(10): 5711–5.PubMedGoogle Scholar
  11. 11.
    Elford HL, Wampler GL, vant Riet B. New ribonucleotide reductase inhibitors with antineoplastic activity. Cancer Res. 1979; 39: 844–51.PubMedGoogle Scholar
  12. 12.
    Davidson JD, Winter TS. A method of analyzing for hydroxyurea in biological fluids. Cancer Chemother Rep. 1963; 27: 97–110.PubMedGoogle Scholar
  13. 13.
    Philips FS, Sternberg SS, Schwartz HS, et al. Hydroxyurea I. Acute cell death in proliferating tissues in rats. Cancer Res. 1967; 27: 61–75.PubMedGoogle Scholar
  14. 14.
    Fabricius E, Rajewsky MF. Determination of hydroxyurea in mammalian tissues and blood. Rev Eur Etud Clin Biol. 1971; 16(7): 679–83.PubMedGoogle Scholar
  15. 15.
    Tracewell WG, Trump DL, Vaughan WP, et al. Population pharmacokinetics of hydroxyurea in cancer patients. Cancer Chemother Pharmacol. 1995; 35(5): 417–22.PubMedCrossRefGoogle Scholar
  16. 16.
    Veale D, Cantwell BMJ, Kerr N, et al. Phase I study of hydroxyurea in lung cancer. Cancer Chemother Pharmacol. 1988; 21(1): 53–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Havard J, Grygiel J, Sampson D. Determination by high-performance liquid chromatography of hydroxyurea in human plasma. J Chromatogr. 1992; 584: 27–4.Google Scholar
  18. 18.
    Villani P, Maserati R, Regazzi MB, et al. Pharmacokinetics of hydroxyurea in patients infected with human immunodeficiency virus type 1. J Clin Pharmacol. 1996; 36: 117–21.PubMedGoogle Scholar
  19. 19.
    Pujari MP, Barrientos A, Muggia FM, et al. Determination of hydroxyurea in plasma and peritoneal fluid by high-performance liquid chromatography using electrochemical detection. J Chromatogr B Biomed Sci Appl. 1997; 694(1): 185–91.PubMedCrossRefGoogle Scholar
  20. 20.
    El-Yazigi A, Al-Rawithi S. Analysis of hydroxyurea in capsules and aqueous solution and stability study with capillary gas chromatography and therminonic (N-P) detection. Pharm Res. 1992; 9(1): 115–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Evered DF, Selhi HS. Transport characteristics of two carcinostatic compounds, hydroxyurea and hadacidin, with rat small intestine [abstract]. Biochem J. 1972; 126: 26P.PubMedGoogle Scholar
  22. 22.
    Adamson RH, Ague SL, Hess SM, et al. The distribution, excretion, and metabolism of hydroxyurea-14C. J Pharmacol Exp Ther. 1965; 150(2): 322–4.PubMedGoogle Scholar
  23. 23.
    Tracewell WG, Vaughan WP, Gwilt PR. Pharmacokinetics of hydroxyurea in the rat [abstract]. Pharm Res 1992; 9 Suppl.: S260.CrossRefGoogle Scholar
  24. 24.
    Belt RJ, Haas CD, Kennedy J, et al. Studies of hydroxyurea administered by continuous infusion: toxicity, pharmacokinetics and cell synchronization. Cancer. 1980; 46(3): 455–62.PubMedCrossRefGoogle Scholar
  25. 25.
    Morgan JS, Creasey DC, Wright JA. Evidence that the antitumor agent hydroxyurea enters mammalian cells by a diffusion mechanism. Biochem Biophys Res Commun. 1986; 134(3): 1254–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Blasberg RG, Patlack C, Fenstermacher JD. Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion. J Pharmacol Exp Ther. 1975; 195: 73–83.PubMedGoogle Scholar
  27. 27.
    Beckloff GL, Lerner HJ, Frost D, et al. Hydroxyurea (NSC-32065) in biologic fluids: dose-concentration relationship. Cancer Chemother Rep. 1965; 48: 57–8.PubMedGoogle Scholar
  28. 28.
    Colvin M, Bono VH. The enzymatic reduction of hydroxyurea to urea by mouse liver. Cancer Res. 1970; 30(5): 1516–9.PubMedGoogle Scholar
  29. 29.
    Andrae U. Evidence for the involvement of cytochrome P-450 dependent monooxygenase (S) in the formation of genotoxic metabolites from N-hydroxyurea. Biochem Biophys Res Commun. 1984; 118(2): 409–15.PubMedCrossRefGoogle Scholar
  30. 30.
    Fishbein WN, Carbone PP. Hydroxyurea: mechanism of action. Science. 1963; 142: 1069–70.PubMedCrossRefGoogle Scholar
  31. 31.
    Van Den Berg CL, McGill JR, Kuhn JG, et al. Pharmacokinetics of hydroxyurea in nude mice. Anticancer Drugs. 1994; 5(5): 573–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Creasey WA, Capizzi RL, DeConti RC. Clinical and biochemical studies of high-dose intermittent therapy of solid tumors with hydroxyurea (NSC-32065). Cancer Chemother Rep. 1970; 54(3): 191–4.PubMedGoogle Scholar
  33. 33.
    Newman EM, Carroll M, Akman SA, et al. Pharmacokinetics and toxicity of 120-hour continuous-infusion hydroxyurea in patients with advanced solid tumors. Cancer Chemother Pharmacol. 1997; 39: 254–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Charache S, Dover GJ, Moore RD, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood. 1992; 79(10): 2555–65.PubMedGoogle Scholar
  35. 35.
    Collins JM. Pharmacological rationales for regional drug delivery. J Clin Oncol. 1984; 2: 498–504.PubMedGoogle Scholar
  36. 36.
    Guyton AC. Textbook of medical physiology. 8th ed. Philadelphia: WB Saunders, 1991: 186.Google Scholar
  37. 37.
    Schilsky RL, Ratain JM, Vokes EE, et al. Laboratory and clinical studies of biochemical modulation by hydroxyurea. Semin Oncol 1992; 19 (3 Suppl. 9): 84–9.PubMedGoogle Scholar
  38. 38.
    Rauscher F, Cadman E. Biochemical and cytokinetic modulation of L1210 and HL-60 cells by hydroxyurea and effect on 1-β-D-arabinofuranosylcytosine metabolism and cytotoxicity. Cancer Res. 1983; 43: 2688–93.PubMedGoogle Scholar
  39. 39.
    Kubota M, Takimoto T, Tanizawa A, et al. Differential modulation of 1-beta-D-arabinofuranosylcytosine metabolism by hydroxyurea in human leukemic cell lines. Biochem Pharmacol. 1988; 37(9): 1745–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Schilsky RL, Williams SF, Ultmann JE, et al. Sequential hydroxyurea-cytarabine chemotherapy for refractory non-Hodgkins lymphoma. J Clin Oncol. 1987; 5(3): 419–25.PubMedGoogle Scholar
  41. 41.
    DeGramont A, Louvet C, Varette C, et al. Reversal of resistance to high-dose folinic acid (LV) and 5-fluorouracil (5-FU) in metastatic colorectal cancer by hydroxyurea [abstract]. Proc Am Soc Clin Oncol. 1992; 11: 178.Google Scholar
  42. 42.
    Heidelberger C, Danenberg PV, Moran RG. Fluorinated pyrimidines and their nucleosides. Adv Enzymol Relat Areas Mol Biol. 1983; 54: 58–119.PubMedGoogle Scholar
  43. 43.
    Li JC, Kaminskas E. Progressive formulation of DNA lesions in cultured Ehrlich ascites tumor cells treated with hydroxyurea. Cancer Res. 1987; 47(11): 2755–8.PubMedGoogle Scholar
  44. 44.
    Minford J, Kerrigan D, Nichols M, et al. Enhancement of the DNA breakage and cytotoxic effects of intercalating agents by treatment with sublethal doses of 1-β-D-arabinofuranosylcytosine or hydroxyurea in L1210 cells. Cancer Res 1984; 44 (12 Pt 1): 5583–93.PubMedGoogle Scholar
  45. 45.
    Ratain MJ, Schilsky RL, Wojack BR, et al. Hydroxyurea and etoposide: in vitro synergy and phase I clinical trial. J Natl Cancer Inst. 1988; 80(17): 1412–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Swinnen LJ, Barnes DM, Fisher SG, et al. 1-β-D-arabinofuranosylcytosine and hydroxyurea production of cytotoxic synergy with cis-diamminedichloroplatinum (II) and modification of platinum-induced DNA inter Strand cross-linking. Cancer Res. 1989; 49(6): 1383–9.PubMedGoogle Scholar
  47. 47.
    Christen RD, Shalinsky DR, Howell SB. Enhancement of the loss of multiple drug resistance by hydroxyurea. Semin Oncol 1992; 19 (3 Suppl. 9): 94–100.PubMedGoogle Scholar
  48. 48.
    Snapka RM, Varshavsky A. Loss of unstably amplified dihydrofolate reductase genes from mouse cells is greatly accelerated by hydroxyurea. Proc Natl Acad Sci U S A. 1983; 80(24): 7533–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Von Hoff DD, Waddelow T, Forseth B, et al. Hydroxyurea accelerates loss of extrachromosomally amplified genes from tumor cells. Cancer Res 1991; 51 (23 Pt 1): 6273–9.Google Scholar
  50. 50.
    Kennedy BJ. Hydroxyurea therapy in chronic myelogenous leukemia. Cancer. 1972; 29(4): 1052–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Sharon R, Tatrsky I, Ben-Arieh Y. Treatment of polycythemia vera with hydroxyurea. Cancer. 1986; 57(4): 718–20.PubMedCrossRefGoogle Scholar
  52. 52.
    Ariel IM. Therapeutic effects of hydroxyurea: an experience with 118 patients with inoperable solid tumors. Cancer. 1970; 25(3): 705–14.PubMedCrossRefGoogle Scholar
  53. 53.
    Carter SK, Wasserman TH. The chemotherapy of urologic cancer. Cancer. 1975; 36: 729–47.PubMedCrossRefGoogle Scholar
  54. 54.
    Mundy AR. A pilot study of hydroxyurea in hormone ‘escaped’ metastatic carcinoma of the prostate. Br J Urol. 1982; 54: 20–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Hussey DH, Abrams JR. Combined therapy in advanced head and neck cancer: hydroxyurea and radiotherapy. Prog Clin Cancer. 1975; 6: 79–86.PubMedGoogle Scholar
  56. 56.
    Hreshchyshyn MM, Aron BS, Boronow RC, et al. Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV cervical cancer confined to the pelvis. Int J Radiat Oncol Biol Phys. 1979; 5: 317–22.PubMedCrossRefGoogle Scholar
  57. 57.
    Piver MS, Vongtama V, Emrich LJ. Hydroxyurea plus pelvic radiation versus placebo plus pelvic radiation in surgically staged state IIIB cervical cancer. J Surg Oncol. 1987; 35(2): 129–34.PubMedCrossRefGoogle Scholar
  58. 58.
    Layton AM, Sheehan-Dare RA, Goodfile MJ, et al. Hydroxyurea in the management of therapy resistant psoriasis. Br J Dermatol. 1989; 121(5): 647–53.PubMedCrossRefGoogle Scholar
  59. 59.
    Lori F, Malykh A, Cara A, et al. Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. Science. 1994; 266: 801–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Griffith KM. Hydroxyurea (NSC-32065): results of a phase I study. Cancer Chemother Rep. 1964; 40: 33–6.PubMedGoogle Scholar
  61. 61.
    Vaughan WP, Kris E, Vose J, et al. Phase I/II study incorporating intravenous hydroxyurea into high-dose chemotherapy for patients with primary refractory or relapsed and refractory intermediate-grade and high-grade malignant lymphoma. J Clin Oncol. 1995; 13(5): 1089–95.PubMedGoogle Scholar
  62. 62.
    Donehower RC. Hydroxyurea. In: Chabner B, editor. Pharmacologic principles of cancer treatment. Philadelphia: WB Saunders, 1982: 269–75.Google Scholar
  63. 63.
    Wilson JG, Scott WJ, Ritter EJ, et al. Comparative distribution and embryotoxicity of hydroxyurea in pregnant rats and rhesus monkeys. Teratology. 1975; 11(2): 169–78.PubMedCrossRefGoogle Scholar
  64. 64.
    Ford SS, Shackney SE. Lethal and sublethal effects of hydroxyurea in relation to drug concentration and duration of drug exposure in sarcoma 180, in vitro. Cancer Res 1977; 37 (8 Pt 1): 2628–37.PubMedGoogle Scholar
  65. 65.
    Moran RE, Straus MJ. Cytokinetic analysis of L1210 leukemia after continuous infusion of hydroxyurea in vivo. Cancer Res. 1979; 39(5): 1616–22.PubMedGoogle Scholar
  66. 66.
    Blumenreich MS, Kellihan MJ, Joseph UG, et al. Long-term intravenous hydroxyurea infusions in patients with advanced cancer: a phase I trial. Cancer. 1993; 71(9): 2828–32.PubMedCrossRefGoogle Scholar
  67. 67.
    Brown PC, Tlsty TD, Schimke RT. Enhancement of methotrexate resistance and dihydrofolate reductase gene amplification by treatment of mouse 3T6 cells in hydroxyurea. Mol Cell Biol. 1983; 3(6): 1097–1107.PubMedGoogle Scholar
  68. 68.
    Dover GJ, Humphries RK, Moore JG, et al. Hydroxyurea induction of hemoglobin F production in sickle cell disease: relationship between cytotoxicity and F cell production. Blood. 1986; 67(3): 735–8.PubMedGoogle Scholar
  69. 69.
    Gao WY, Johns DG, Chokekijchai S, et al. Disparate actions of hydroxyurea in potentiation of purine and pyrimidine 2′,3′-dideoxynucleoside activities against replication of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1995; 92: 8333–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Malley SD, Grange JM, Hamedi-Sangsari F, et al. Synergistic anti-human immunodeficiency virus type 1 effect of hydroxamate compounds with 2,3-dideoxyinosine in infected resting human lymphocytes. Proc Natl Acad Sci U S A. 1994; 91: 11017–21.PubMedCrossRefGoogle Scholar
  71. 71.
    Giacca M, Zanussi S, Comar M, et al. Treatment of human immunodeficiency virus infection with hydroxyurea: virologic and clinical evaluation. J Infect Dis. 1996; 174: 204–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Simonelli C, Nasti G, Vaccher E, et al. Hydroxyurea treatment in HIV-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol. 1996; 13: 462–4.PubMedCrossRefGoogle Scholar
  73. 73.
    Biron F, Lucht F, Peyramond D, et al. Anti-HIV activity of the combination of didanosine and hydroxyurea in HIV-1-in-fected individuals. J Acquir Immune Defic Syndr Hum Retrovirol. 1995; 10: 36–40.PubMedGoogle Scholar
  74. 74.
    Vila J, Biron F, Nugier F, et al. 1-year follow-up of the use of hydroxycarbamide and didanosine in HIV infection. Lancet. 1996; 348(9021): 203–4.PubMedCrossRefGoogle Scholar
  75. 75.
    Montaner JSG, Zala C, Conway B, et al. A pilot study of hydroxyurea among patients with advanced human immunodeficiency virus (HIV) disease receiving chronic didanosine therapy: Canadian HIV trials network protocol 080. J Infect Dis. 1997; 175: 801–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Malley SD, Grange JM, Hamedi-Sangsari F, et al. Suppression of HIV production in resting lymphocytes by combining didanosine and hydroxamate compounds [abstract]. Lancet. 1994; 343: 1292.PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.MDS HarrisLincolnUSA

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