Chemo Fog pp 124-132 | Cite as

Pharmacokinetics of Anti-Cancer Drugs Used in Breast Cancer Chemotherapy

  • Swati Nagar
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 678)


Pharmacokinetics of anticancer drugs used in breast cancer therapy are well established. This chapter reviews preclinical and clinical pharmacokinetics of the following drugs: cyclophosphamide, docetaxel, doxorubicin, 5-fluorouracil, methotrexate and tam oxifen. The absorption, distribution, metabolism and elimination of drugs are discussed in the context of breast cancer. The effect of age and menopause status on drug pharmacokinetics is evaluated. The important role of pharmacokinetic-pharmacodynamic modeling in understanding the phenomenon of chemo fog, memory deficit in breast cancer chemotherapy, is explored.


Breast Cancer Acute Lymphoblastic Leukemia Anticancer Drug Liposomal Doxorubicin Breast Cancer Therapy 
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  1. 1.
    Ekhart C, Doodeman VD, Rodenhuis S et al. Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide. Pharmacogenet Genomics 2008; 18(6):515–23.PubMedCrossRefGoogle Scholar
  2. 2.
    Roy P, Yu LJ, Crespi CL et al. Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos 1999; 27(6):655–66.PubMedGoogle Scholar
  3. 3.
    de Jonge ME, Huitema AD, Rodenhuis S et al. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 2005; 44(11):1135–64.PubMedCrossRefGoogle Scholar
  4. 4.
    Pass GJ, Carrie D, Boylan M et al. Role of hepatic cytochrome p450s in the pharmacokinetics and toxicity of cyclophosphamide: studies with the hepatic cytochrome p450 reductase null mouse. Cancer Res 2005; 65(10):4211–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Gu J, Chen CS, Wei Y et al. A mouse model with liver-specific deletion and global suppression of the NADPH-cytochrome P450 reductase gene: characterization and utility for in vivo studies of cyclophosphamide disposition. J Pharmacol Exp Ther 2007; 321(1):9–17.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Bang SM, Heo DS, Lee KH et al. Adjuvant doxorubicin and cyclophosphamide versus cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy in premenopausal women with axillary lymph node positive breast carcinoma. Cancer 2000; 89(12):2521–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Xie H, Griskevicius L, Stahle L et al. Pharmacogenetics of cyclophosphamide in patients with hematological malignancies. Eur J Pharm Sci 2006; 27(1):54–61.PubMedCrossRefGoogle Scholar
  8. 8.
    Nakajima M, Komagata S, Fujiki Y et al. Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/ pharmacodynamics of cyclophosphamide in Japanese cancer patients. Pharmacogenet Genomics 2007; 17(6):431–45.PubMedCrossRefGoogle Scholar
  9. 9.
    Fulton B, Spencer CM. Docetaxel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of metastatic breast cancer. Drugs 1996; 51(6):1075–92.PubMedCrossRefGoogle Scholar
  10. 10.
    Baker SD, Sparreboom A, Verweij J. Clinical pharmacokinetics of docetaxel: recent developments. Clin Pharmacokinet 2006; 45(3):235–52.PubMedCrossRefGoogle Scholar
  11. 11.
    Clarke SJ, Rivory LP. Clinical pharmacokinetics of docetaxel. Clin Pharmacokinet 1999; 36(2):99–114.PubMedCrossRefGoogle Scholar
  12. 12.
    Schellens JH, Malingre MM, Kruijtzer CM et al. Modulation of oral bioavailability of anticancer drugs: from mouse to man. Eur J Pharm Sci 2000; 12(2):103–10.PubMedCrossRefGoogle Scholar
  13. 13.
    Sparreboom A, van Tellingen O, Nooijen WJ et al. Preclinical pharmacokinetics of paclitaxel and docetaxel. Anticancer Drugs 1998; 9(1):1–17.PubMedCrossRefGoogle Scholar
  14. 14.
    Bardelmeijer HA, Ouwehand M, Buckle T et al. Low systemic exposure of oral docetaxel in mice resulting from extensive first-pass metabolism is boosted by ritonavir. Cancer Res 2002; 62(21):6158–64.PubMedGoogle Scholar
  15. 15.
    ten Tije AJ, Verweij J, Carducci MA et al. Prospective evaluation of the pharmacokinetics and toxicity profile of docetaxel in the elderly. J Clin Oncol 2005; 23(6):1070–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Gabizon A, Shmeeda H, Barenholz Y. Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies. Clin Pharmacokinet 2003; 42(5):419–36.PubMedCrossRefGoogle Scholar
  17. 17.
    Kivisto KT, Kroemer HK, Eichelbaum M. The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions. Br J Clin Pharmacol 1995; 40(6):523–30.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Zordoky BN, El-Kadi AO. Induction of several cytochrome P450 genes by doxorubicin in H9c2 cells. Vascul Pharmacol 2008; 49(4–6):166–72.CrossRefGoogle Scholar
  19. 19.
    Charrois GJ, Allen TM. Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer. Biochim Biophys Acta 2004; 1663(1–2):167–77.PubMedCrossRefGoogle Scholar
  20. 20.
    Hong RL, Huang CJ, Tseng YL et al. Direct comparison of liposomal doxorubicin with or without polyethylene glycol coating in C-26 tumor-bearing mice: is surface coating with polyethylene glycol beneficial? Clin Cancer Res 1999; 5(11):3645–52.PubMedGoogle Scholar
  21. 21.
    Fujisaka Y, Horiike A, Shimizu T et al. Phase 1 clinical study of pegylated liposomal doxorubicin ( JNS002) in Japanese patients with solid tumors. Jpn J Clin Oncol 2006; 36(12):768–74.PubMedCrossRefGoogle Scholar
  22. 22.
    Varela M, Real MI, Burrel M et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 2007; 46(3):474–81.PubMedCrossRefGoogle Scholar
  23. 23.
    Chabner BA, Ryan DP, Paz-Ares L et al. Antineoplastic Agents in Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001.Google Scholar
  24. 24.
    Ooi A, Ohkubo T, Higashigawa M et al. Plasma, intestine and tumor levels of 5-fluorouracil in mice bearing L1210 ascites tumor following oral administration of 5-fluorouracil, UFT (mixed compound of tegafur and uracil), carmofur and 5′-deoxy-5-fluorouridine. Biol Pharm Bull 2001; 24(11):1329–31.PubMedCrossRefGoogle Scholar
  25. 25.
    Jin Y, Li J, Rong LF et al. Pharmacokinetics and tissue distribution of 5-fluorouracil encapsulated by galactosylceramide liposomes in mice. Acta Pharmacol Sin 2005; 26(2):250–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Grem JL, Quinn M, Ismail AS et al. Pharmacokinetics and pharmacodynamic effects of 5-fluorouracil given as a one-hour intravenous infusion. Cancer Chemother Pharmacol 2001; 47(2):117–25.PubMedCrossRefGoogle Scholar
  27. 27.
    Gusella M, Crepaldi G, Barile C et al. Pharmacokinetic and demographic markers of 5-fluorouracil toxicity in 181 patients on adjuvant therapy for colorectal cancer. Ann Oncol 2006; 17(11):1656–60.PubMedCrossRefGoogle Scholar
  28. 28.
    Song JG, Nakano S, Ohdo S et al. Chronotoxicity and chronopharmacokinetics of methotrexate in mice: modification by feeding schedule. Jpn J Pharmacol 1993; 62(4):373–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Ohdo S, Inoue K, Yukawa E et al. Chronotoxicity of methotrexate in mice and its relation to circadian rhythm of DNA synthesis and pharmacokinetics. Jpn J Pharmacol 1997; 75(3):283–90.PubMedCrossRefGoogle Scholar
  30. 30.
    Lobo ED, Balthasar JP. Pharmacokinetic-pharmacodynamic modeling of methotrexate-induced toxicity in mice. J Pharm Sci 2003; 92(8):1654–64.PubMedCrossRefGoogle Scholar
  31. 31.
    Rau T, Erney B, Gores R et al. High-dose methotrexate in pediatric acute lymphoblastic leukemia: impact of ABCC2 polymorphisms on plasma concentrations. Clin Pharmacol Ther 2006; 80(5):468–76.PubMedCrossRefGoogle Scholar
  32. 32.
    Plard C, Bressolle F, Fakhoury M et al. A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 2007; 60(4):609–20.PubMedCrossRefGoogle Scholar
  33. 33.
    DeGregorio MW, Wilbur BJ, Coronado E et al. Serum tamoxifen concentrations in the athymic nude mouse after three methods of administration. Cancer Chemother Pharmacol 1987; 20(4):316–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Robinson SP, Langan-Fahey SM, Johnson DA et al. Metabolites, pharmacodynamics and pharmacokinetics of tamoxifen in rats and mice compared to the breast cancer patient. Drug Metab Dispos 1991; 19(1):36–43.PubMedGoogle Scholar
  35. 35.
    Dowsett M, Cuzick J, Howell A et al. Pharmacokinetics of anastrozole and tamoxifen alone and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: a sub-protocol of the ‘Arimidex and tamoxifen alone or in combination’ (ATAC) trial. Br J Cancer 2001; 85(3):317–24.PubMedCrossRefGoogle Scholar
  36. 36.
    Bergan RC, Reed E, Myers CE et al. A Phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer. Clin Cancer Res 1999; 5(9):2366–73.PubMedGoogle Scholar
  37. 37.
    Hutson PR, Love RR, Havighurst TC et al. Effect of exemestane on tamoxifen pharmacokinetics in postmenopausal women treated for breast cancer. Clin Cancer Res 2005; 11(24 Pt 1):8722–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Ingle JN, Suman VJ, Johnson PA et al. Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer. Clin Cancer Res 1999; 5(7):1642–9.PubMedGoogle Scholar
  39. 39.
    Kisanga ER, Gjerde J, Guerrieri-Gonzaga A et al. Tamoxifen and metabolite concentrations in serum and breast cancer tissue during three dose regimens in a randomized preoperative trial. Clin Cancer Res 2004; 10(7):2336–43.PubMedCrossRefGoogle Scholar
  40. 40.
    Kisanga ER, Gjerde J, Schjott J et al. Tamoxifen administration and metabolism in nude mice and nude rats. J Steroid Biochem Mol Biol 2003; 84(2–3):361–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Hurria A, Lichtman SM. Pharmacokinetics of chemotherapy in the older patient. Cancer Control 2007; 14(1):32–43.PubMedGoogle Scholar
  42. 42.
    Yuen GJ. Altered pharmacokinetics in the elderly. Clin Geriatr Med 1990; 6(2):257–67.PubMedGoogle Scholar
  43. 43.
    Baker SD, Grochow LB. Pharmacology of cancer chemotherapy in the older person. Clin Geriatr Med 1997; 13(1):169–83.PubMedGoogle Scholar
  44. 44.
    Hamberg P, Verweij J, Seynaeve C. Cytotoxic therapy for the elderly with metastatic breast cancer: a review on safety, pharmacokinetics and efficacy. Eur J Cancer 2007; 43(10):1514–28.PubMedCrossRefGoogle Scholar
  45. 45.
    Ortmann O, Cufer T, Dixon JM et al. Adjuvant endocrine therapy for perimenopausal women with early breast cancer. Breast 2009; 18(1):2–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Utsumi T, Kobayashi N, Hanada H. Recent perspectives of endocrine therapy for breast cancer. Breast Cancer 2007; 14(2):194–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Levin J, Markham MJ, Greenwald ES et al. Effect of tamoxifen treatment on estrogen metabolism in postmenopausal women with advanced breast cancer. Anticancer Res 1982; 2(6):377–80.PubMedGoogle Scholar
  48. 48.
    Sparks R, Ulrich CM, Bigler J et al. UDP-glucuronosyltransferase and sulfotransferase polymorphisms, sex hormone concentrations and tumor receptor status in breast cancer patients. Breast Cancer Res 2004; 6(5):R488–98.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Nagar S, Remmel RP. Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer. Oncogene 2006; 25(11):1659–72.PubMedCrossRefGoogle Scholar
  50. 50.
    Nagar S, Walther S, Blanchard RL. Sulfotransferase (SULT) 1A1 polymorphic variants *1, *2 and *3 are associated with altered enzymatic activity, cellular phenotype and protein degradation. Mol Pharmacol 2006; 69(6):2084–92.PubMedCrossRefGoogle Scholar
  51. 51.
    Gjerde J, Hauglid M, Breilid H et al. Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism. Ann Oncol 2008; 19(1):56–61.PubMedCrossRefGoogle Scholar
  52. 52.
    Ohtake E, Kakihara F, Matsumoto N et al. Frequency distribution of phenol sulfotransferase 1A1 activity in platelet cells from healthy Japanese subjects. Eur J Pharm Sci 2006; 28(4):272–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Nelson CJ, Nandy N, Roth AJ. Chemotherapy and cognitive deficits: mechanisms, findings and potential interventions. Palliat Support Care 2007; 5(3):273–80.PubMedCrossRefGoogle Scholar
  54. 54.
    Jenkins V, Atkins L, Fallowfield L. Does endocrine therapy for the treatment and prevention of breast cancer affect memory and cognition? Eur J Cancer 2007; 43(9):1342–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Palmer JL, Trotter T, Joy AA et al. Cognitive effects of Tamoxifen in premenopausal women with breast cancer compared to healthy controls. J Cancer Surviv 2008; 2(4):275–82.PubMedCrossRefGoogle Scholar
  56. 56.
    Jim HS, Donovan KA, Small BJ et al. Cognitive functioning in breast cancer survivors: a controlled comparison. Cancer 2009; 115(8):1776–83.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  • Swati Nagar
    • 1
  1. 1.Temple University School of PharmacyPhiladelphiaUSA

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