Clinical Pharmacokinetics

, Volume 38, Issue 4, pp 291–304 | Cite as

Metabolism and Pharmacokinetics of Oxazaphosphorines

Review Article Drug Disposition

Abstract

The 2 most commonly used oxazaphosphorines are cyclophosphamide and ifosfamide, although other bifunctional mustard analogues continue to be investigated. The pharmacology of these agents is determined by their metabolism, since the parent drug is relatively inactive. For cyclophosphamide, elimination of the parent compound is by activation to the 4-hydroxy metabolite, although other minor pathways of inactivation also play a role. Ifosfamide is inactivated to a greater degree by dechloroethylation reactions. More robust assay methods for the 4-hydroxy metabolites may reveal more about the clinical pharmacology of these drugs, but at present the best pharmacodynamic data indicate an inverse relationship between plasma concentration of parent drug and either toxicity or antitumour effect.

The metabolism of cyclophosphamide is of particular relevance in the application of high dose chemotherapy. The activation pathway of metabolism is saturable, such that at higher doses (greater than 2 to 4 g/m2) a greater proportion of the drug is eliminated as inactive metabolites. However, both cyclophosphamide and ifosfamide also act to induce their own metabolism. Since most high dose regimens require a continuous infusion or divided doses over several days, saturation of metabolism may be compensated for, in part, by auto-induction. Although a quantitative distinction may be made between the cytochrome P450 isoforms responsible for the activating 4-hydroxylation reaction and those which mediate the dechloroethylation reactions, selective induction of the activation pathway, or inhibition of the inactivating pathway, has not been demonstrated clinically.

Mathematical models to describe and predict the relative contributions of saturation and autoinduction to the net activation of cyclophosphamide have been developed. However, these require careful validation and may not be applicable outside the exact regimen in which they were derived. A further complication is the chiral nature of these 2 drugs, with some suggestion that one enantiomer may have a favourable profile of metabolism over the other.

That the oxazaphosphorines continue to be the subject of intensive investigation over 30 years after their introduction into clinical practice is partly because of their antitumour activity. Further advances in analytical and molecular pharmacological techniques may further optimise their use and allow rational design of more selective analogues.

Keywords

Cyclophosphamide Ifosfamide Parent Drug Mesna Haemorrhagic Cystitis 

References

  1. 1.
    Brock N. Oxazaphosphorine cytostatics: past-present-future. Cancer Res 1989; 49: 1–7PubMedGoogle Scholar
  2. 2.
    Colvin M. The comparative pharmacology of cyclophosphamide and ifosfamide. Semin Oncol 1982; 9: 2–7PubMedGoogle Scholar
  3. 3.
    Kusniercysk H, Radzikowski C, Paprocka M, et al. Antitumor activity of optical isomers of cyclophosphamide, ifosfamide and trofosfamide as compared to clinically used racemates. J Immunophannacol 1986; 8: 455–80CrossRefGoogle Scholar
  4. 4.
    Wagner A, Hempel G, Boos J. Trofosfamide: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential int the oral treatment of cancer. Anticancer Drugs 1997; 8: 419–31PubMedCrossRefGoogle Scholar
  5. 5.
    Schomburg A, Menzel T, Hadam M, et al. Biologic and therapeutic efficacy of mafosfamide in patients with metastatic renal cell carcinoma. Mol Biother 1992; 4: 58–65PubMedGoogle Scholar
  6. 6.
    Veyhl M, Wagner K, Volk C, et al. Transport of the new chemotherapeutic agent beta-D-glucosylisophosphamide mustard (D-19575) into tumor cells is mediated by the Na+-D-glucose cotransporter SAAT1. Proc Natl Acad Sci USA 1998; 95: 2914–9PubMedCrossRefGoogle Scholar
  7. 7.
    Phillips PC, Than TT, Cork LC, et al. Intrathecal 4-hydroperoxycyclophosphamide: neurotoxicity, cerebrospinal fluid pharmacokinetics and antitumor activity in a rabbit model of VX2 leptomeningeal carcinomatosis. Cancer Res 1992; 52: 6168–74PubMedGoogle Scholar
  8. 8.
    Passos-Cohellho J, Ross AA, Davis JM, et al. Bone marrow micrometastases in chemotherapy-responsive advanced breast cancer: effect of ex vivo purging with 4-hydroperoxycyclophosphamide. Cancer Res 1994; 54: 2366–71Google Scholar
  9. 9.
    MayManke A, Kroemer H, Hempel G, et al. Investigation of the major human hepatic cytochrome P450 involved in 4-hydroxylation and N-dechloroethylation of trofosfamide. Cancer Chemother Pharmacol 1999; 44: 327–34CrossRefGoogle Scholar
  10. 10.
    Moore MJ. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 1991; 20: 194–208PubMedCrossRefGoogle Scholar
  11. 11.
    Kaijser GP, Beijnen JH, Bult A, et al. Ifosfamide metabolism and pharmacokinetics [review]. Anticancer Res 1994; 14: 517–32PubMedGoogle Scholar
  12. 12.
    Wagner T. Ifosfamide clinical pharmacokinetics. Clin Pharmacokinet 1994; 26: 439–56PubMedCrossRefGoogle Scholar
  13. 13.
    Fleming RA. An overview of cyclophosphamide and ifosfamide pharmacology. Pharmacotherapy 1997; 5 (Pt 2): S146–54Google Scholar
  14. 14.
    Kohn KW, Hartley JA, Mattes WB. Mechanisms of DNA sequence alkylation of guanine-N7 positions by nitrogen mustards. Nucl Acid Res 1987; 14: 10531–45CrossRefGoogle Scholar
  15. 15.
    Springer JB, Colvin ME, Colvin OM, et al. Isophosphoramide mustard and its mechanism of bisalkylation. J Org Chem 1998; 63: 7218–22PubMedCrossRefGoogle Scholar
  16. 16.
    Shulman Roskes EM, Noe DA, Gamcsik MP, et al. The partitioning of phosphoramide mustard and its aziridinium ions among alkylation and P-N bond hydrolysis reactions. J Med Chem 1998; 41: 515–29PubMedCrossRefGoogle Scholar
  17. 17.
    O’Connor PM, Wassermann K, Sarnag M. Relationship between DNA cross-links, cell cycle and apoptosis in Burkitt’s lymphoma cell lines differing in sensitivity to nitrogen mustard. Cancer Res 1991; 51: 6550–7PubMedGoogle Scholar
  18. 18.
    Hickman JA. Apoptosis and cancer chemotherapy. Cancer Metastasis Rev 1992; 11: 121–39PubMedCrossRefGoogle Scholar
  19. 19.
    Crook TR, Souhami RL, Whyman GD, et al. Glutathione depletion as a determinant of sensitivity of human leukaemia cells to cyclophosphamide. Cancer Res 1986; 46: 5035–8PubMedGoogle Scholar
  20. 20.
    Richardson ME, Siemann DW. DNA damage in cyclophosphamide-resistant tumor cells: the role of glutathione. Cancer Res 1995; 55: 1691–5PubMedGoogle Scholar
  21. 21.
    Andersson BS, Mroue M, Britten RA, et al. The role of DNA damage in the resistance of human chronic myeloid leukaemia cells to cyclophosphamide analogues. Cancer Res 1994; 54: 5394–400PubMedGoogle Scholar
  22. 22.
    Dong Q, Bullock N, Ali-Osman F, et al. Repair analysis of 4-hydroperoxycyclophosphamide-induced DNA interstrand cross-linking in the c-myc gene in 4-hydrocyclophosphamide-sensitive and resistant cell lines. Cancer Chemother Pharmacol 1996; 37: 242–6PubMedCrossRefGoogle Scholar
  23. 23.
    Maki PA, Sladek NE. Sensitivity of aldehyde dehydrogenases in murine tumor and hematopoietic progenitor cells to inhibition by chloral hydrate to potentiate the cytotoxic action of mafosfamide. Biochem Pharmacol 1993; 45: 231–9PubMedCrossRefGoogle Scholar
  24. 24.
    Sreerama L, Sladek NE. Identification and characterization of a novel class 3 aldehyde dehydrogenase overexpressed in a human breast adenocarcinoma cell line exhibiting oxazaphosphorine-specific acquired resistance. Biochem Pharmacol 1993; 45: 2487–505PubMedCrossRefGoogle Scholar
  25. 25.
    Sreerama L, Sladek NE. Identification of the class-3 aldehyde dehydrogenases present in human MCF-7/0 breast adenocarcinoma cells and normal human breast tissue. Biochem Pharmacol 1994; 48: 617–20PubMedCrossRefGoogle Scholar
  26. 26.
    Magni M, Shammah S, Schiro R, et al. Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. Blood 1996; 87: 1097–103PubMedGoogle Scholar
  27. 27.
    Dole MG, Jasty R, Cooper MJ, et al. Bcl-xl is expressed in neuroblastoma cells and modulates chemotherapy-induced apoptosis. Cancer Res 1995; 55: 2576–82PubMedGoogle Scholar
  28. 28.
    Friedman HS, Pegg AE, Johnson SP, et al. Modulation of cyclophosphamide activity by O-6-alkylguanine-DNA alkyltransferase. Cancer Chemother Pharmacol 1999; 43: 80–5PubMedCrossRefGoogle Scholar
  29. 29.
    Bonadonna G, Valagussa P, Moliterni A, et al. Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-positive breast cancer. N Engl J Med 1995; 332: 901–6PubMedCrossRefGoogle Scholar
  30. 30.
    Fisher B, Anderson S, Wickerham DL, et al. Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from the national surgical adjuvant breast and bowel project B-22. J Clin Oncol 1997; 15: 1858–69PubMedGoogle Scholar
  31. 31.
    Murphy SB, Bowman WP, Cooper MJ, et al. Results of treatment of advanced stage Burkitts lymphoma and B-cell (Sig+) acute lymphoblastic leukaemia with high dose fractionated cyclophosphamide and co-ordinated high-dose methotrexate and cytarabine. J Clin Oncol 1986; 4: 1732–9PubMedGoogle Scholar
  32. 32.
    Reiter A, Achrappe M, Ludwig W-D, et al. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86. Blood 1994; 84: 3122–33PubMedGoogle Scholar
  33. 33.
    Frei E, Teicher BA, Holden SA, et al. Preclinical studies and clinical correlation of the effect of alkylating dose. Cancer Res 1988; 48: 6417–23PubMedGoogle Scholar
  34. 34.
    Teicher BA, Cucchi CA, Lee JB, et al. In vitro studies of cross-resistance patterns in human cell lines. Cancer Res 1986; 46: 4379–83PubMedGoogle Scholar
  35. 35.
    Lilley ER, Rosenberg MC, Elion GB, et al. Synergistic interactions between cyclophosphamide or melphalan and VP-16 in a human rhabdomyosarcomaxenograft. Cancer Res 1990; 15: 284–7Google Scholar
  36. 36.
    Zecca M, Pession A, Bonetti F, et al. Total body irradiation, thiotepa and cyclophosphamide as a conditioning regimen for children with acute lymphoblastic leukemia in first or second remission undergoing bone marrow transplantation with HLA-identical siblings. J Clin Oncol 1999; 17: 1838–46PubMedGoogle Scholar
  37. 37.
    Klein HO, Wickramanayake PD, Christian E, et al. Therapeutic effects of single-push or fractionated injections or continuous infusion of oxazaphosphorines (cyclophosphamide, Ifosfamide and Asta Z 7557). Cancer 1984; 54: 1193–203PubMedCrossRefGoogle Scholar
  38. 38.
    Juma FD, Rogers HJ, Trounce JR, et al. Pharmacokinetics of intravenous cyclophosphamide in man, estimated by gas-liquid chromatography. Cancer Chemother Pharmacol 1978; 1: 229–31PubMedCrossRefGoogle Scholar
  39. 39.
    Jardine I, Fenselau C, Appier M, et al. Quantitation by gas chromatography-chemical ionization mass spectrometry of cyclophosphamide, phosphoramide mustard, and nornitrogen mustard in the plasma and urine of patients receiving cyclophosphamide therapy. Cancer Res 1978; 38: 408–15PubMedGoogle Scholar
  40. 40.
    Motzer RJ, Gulati SC, Tong WP, et al. Phase I trial with pharmacokinetic analyses of high-dose carboplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation in patients with refractory germ cell tumors. Cancer Res 1993; 53: 3730–5PubMedGoogle Scholar
  41. 41.
    Momerency G, van Cauwenberghe K, Slee PHTJ, et al. The determination of cyclophosphamide and its metabolites in blood plasma as stable trifluoroacetyl derivatives by electron capture chemical ionization gas chromatography/mass spectrometry. Biol Mass Spectrom 1996; 23: 149–58CrossRefGoogle Scholar
  42. 42.
    Ludeman SM, Shulman Roskes EM, Wong KKT, et al. Oxime derivatives of the intermediary oncostatic metabolites of cyclophosphamide and ifosfamide: synthesis and deuterium labeling for applications to metabolite quantification. J Pharm Sci 1995; 84: 393–8PubMedCrossRefGoogle Scholar
  43. 43.
    Kerbusch T, Huitema ADR, Kettenesvanden Bosch JJ, et al. High-performance liquid chromatographic determination of stabilized 4-hydroxyifosfamide in human plasma and erythrocytes. J Chromatogr B 1998; 716: 275–84CrossRefGoogle Scholar
  44. 44.
    Slattery JT, Kalhorn TF, McDonald GB, et al. Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients. J Clin Oncol 1996; 14: 1484–94PubMedGoogle Scholar
  45. 45.
    Baumann F, Lorenz C, Jaehde U, et al. Determination of cyclophosphamide and its metabolites in human plasma by highperformance liquid chromatography-mass spectrometry. J Chromatogr B 1999; 729: 297–305CrossRefGoogle Scholar
  46. 46.
    Joqueviel C, Gilard V, Martino R, et al. Urinary stability of carboxycyclophosphamide and carboxyifosfamide, two major metabolites of the anticancer drugs cyclophosphamide and ifosfamide. Cancer Chemother Pharmacol 1997; 40: 391–9PubMedCrossRefGoogle Scholar
  47. 47.
    Reid JM, Stobaugh JF, Sternson LA. Liquid chromatographic determination of cyclophosphamide enantiomers in plasma by precolumn chiral derivatization. Anal Chem 1989; 61: 441–6PubMedCrossRefGoogle Scholar
  48. 48.
    Masurel D, Wainer IW. Analytical and preparative high-performance liquid chromatographic separation of the enantiomers of ifosfamide, cyclophosphamide and trofosfamide and their determination in plasma. J Chromatogr Biomed Appl 1989; 490: 133–43CrossRefGoogle Scholar
  49. 49.
    Struck RF, Alberts DS, Home K, et al. Plasma pharmacokinetics of cyclophosphamide and its cytotoxic metabolites after intravenous versus oral administration in a randomized, crossover trial. Cancer Res 1987; 47: 2732–26Google Scholar
  50. 50.
    Juma FD, Rogers HJ, Trounce JR. Pharmacokinetics of cyclophosphamide and alkylating activity in man after intravenous and oral administration. Br J Clin Pharmacol 1979; 8: 209–17PubMedCrossRefGoogle Scholar
  51. 51.
    De Bruijn EA, Slee PHYJ, van Oosteron AT, et al. Pharmacokinetics of intravenous and oral cyclophosphamide in the presence of methotrexate and flourouracil. Pharm Weekbl 1988; 10: 200–6CrossRefGoogle Scholar
  52. 52.
    Houghton PJ, Tew KD, Taylor DM. Sudies on the distribution and effects of cyclophosphamide in normal and neoplastic tissues. Cancer Treat Rep 1976; 60: 459–64PubMedGoogle Scholar
  53. 53.
    Powis G, Reece P, Ahmann DL, et al. Effect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients. Cancer Chemother Pharmacol 1987; 20: 219–22PubMedCrossRefGoogle Scholar
  54. 54.
    Homines OR, Aerts F, Bahr U, et al. Cyclophosphamide levels in serum and spinal fluid of multiple sclerosis patients treated with immunosuppression. J Neurol Sci 1983; 85: 297–303CrossRefGoogle Scholar
  55. 55.
    Neuwelt EA, Barnett PA, Frenkel ER. Chemotherapeutic agents’ permeability to normal brain and delivery to avian sarcoma virus-induced brain tumours in the rodent: observations on problems of drug delivery. Neurosurgery 1984; 14: 154–60PubMedCrossRefGoogle Scholar
  56. 56.
    Yule SM, Price L, Pearson ADJ, et al. Cyclophosphamide and ifosfamide metabolites in the cerebrospinal fluid of children. Clin Cancer Res 1997; 3: 1985–92PubMedGoogle Scholar
  57. 57.
    Mahoney DH, Strother D, Camitta B, et al. High dose melphalan and cyclophosphamide with autologous bone marrow rescue for recurrent/progressive malignant brain tumours in children: a pilot pediatric oncology group study. J Clin Oncol 1996; 14: 382–8PubMedGoogle Scholar
  58. 58.
    Fasola G, Lo Greco P, Calori E, et al. Pharmacokinetics of highdose cyclophosphamide for bone marrow transplantation. Haematologica 1991; 76: 120–5PubMedGoogle Scholar
  59. 59.
    Bailey H, Mulcahy RT, Tutsch KD, et al. A phase I study of SR-2508 and cyclophosphamide administered by intravenous injection. Cancer Res 1991; 51: 1099–104PubMedGoogle Scholar
  60. 60.
    Dooley JS, James CA, Rogers HJ, et al. Biliary elimination of cyclophosphamide in man. Cancer Chemother Pharmacol 1982; 9: 26–9PubMedCrossRefGoogle Scholar
  61. 61.
    Dockam PA, Sreerama L, Sladek NE. Relative contribution of human erythrocyte aldehyde dehydrogenase to the systemic detoxicification of the oxazaphosphorines. Drug Metab Disp 1997; 25: 1436–41Google Scholar
  62. 62.
    Chen I, Waxman D. Intratumoral activation and enhanced chemotherapeutic effect of oxazaphosphorines following cytochrome P450 gene-transfer — development of a combined chemotherapy cancer gene-therapy strategy. Cancer Res 1995; 55: 581–9PubMedGoogle Scholar
  63. 63.
    Sladek N. Metabolism of oxazaphosphorines. Pharmacol Ther 1988; 37: 301–55PubMedCrossRefGoogle Scholar
  64. 64.
    Chang TKH, Weber GF, Crespi CL, et al. Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Cancer Res 1993; 53: 5629–37PubMedGoogle Scholar
  65. 65.
    Fenselau C, Kan M-NN, Subba Rao S, et al. Identification of aldophsophamide as a metabolite of cyclophosphamide in vitro and in vivo in humans. Cancer Res 1977; 37: 2538–43PubMedGoogle Scholar
  66. 66.
    Dockham PA, Lee M-O, Sladek NE. Identification of human liver aldehyde dehydrogenases that catalyze the oxidation of aldophosphamide and retinaldehyde. Biochem Pharmacol 1992; 43: 2453–69PubMedCrossRefGoogle Scholar
  67. 67.
    Bohnenstengel F, Hofmann U, Eichelbaum M, et al. Characterization of the cytochrome p450 involved in side-chain oxidation of cyclophosphamide in humans. Eur J Clin Pharmacol 1996; 51: 297–301PubMedCrossRefGoogle Scholar
  68. 68.
    Ren S, Yang JS, Kalhorn TF, et al. Oxidation of cyclophosphamide to 4-hydroxycyclophosphamide and deschloroethyl-cyclophosphamide in human liver microsomes. Cancer Res 1997; 57: 4229–35PubMedGoogle Scholar
  69. 69.
    Boddy AV, Furtun Y, Sardas S, et al. Individual variation in the activation and inactivation metabolic pathways of cyclophosphamide. J Natl Cancer Inst 1992; 84: 1744–8PubMedCrossRefGoogle Scholar
  70. 70.
    Hadidi A-HFA, Coulter CEA, Idle JR. Phenotypically deficient urinary elimination of carboxyphosphamide after cyclophosphamide administration to cancer patients. Cancer Res 1988; 48: 5167–71PubMedGoogle Scholar
  71. 71.
    Yule SM, Boddy AV, Cole M, et al. Cyclophosphamide metabolism in children. Cancer Res 1995; 55: 803–9PubMedGoogle Scholar
  72. 72.
    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 profiles. Drug Metab Disp 1999; 27: 655–66Google Scholar
  73. 73.
    Moore MJ, Ehrlichman C, Thiessen JJ, et al. Variability in the pharmacokinetics of cyclophosphamide, methotrexate and 5-fluorouracil in women receiving adjuvant treatment for breast cancer. Cancer Chemother Pharmacol 1994; 33: 472–6PubMedCrossRefGoogle Scholar
  74. 74.
    Yule SM, Boddy AV, Cole M, et al. Cyclophosphamide pharmacokinetics in children. Br J Clin Pharmacol 1996; 41: 13–9PubMedCrossRefGoogle Scholar
  75. 75.
    Yule SM, Walker D, Cole M, et al. The effect of fluconazole on cyclophosphamide metabolism in children. Drug Metab Disp 1999; 27: 417–21Google Scholar
  76. 76.
    Chen T-L, Passos-Coelho J, Noe D, et al. Nonlinear pharmacokinetics of cyclophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation. Cancer Res 1995; 55: 810–6PubMedGoogle Scholar
  77. 77.
    Busse D, Busch FW, Bohnenstengel F, et al. Dose escalation of cyclophosphamide in patients with breast cancer: Consequences for pharmacokinetics and metabolism. J Clin Oncol 1997; 15: 1885–96PubMedGoogle Scholar
  78. 78.
    Bramwell V, Calvert RT, Edwards G, et al. The disposition of cyclophosphamide in a group of myeloma patients. Cancer Chemother Pharmacol 1979; 3: 253–9PubMedCrossRefGoogle Scholar
  79. 79.
    Juma FD, Rogers HJ, Trounce JR. Effect of renal insufficiency on the pharmacokinetics of cyclophosphamide and some of its metabolites. Eur J Clin Pharmacol 1981; 19: 443–51PubMedCrossRefGoogle Scholar
  80. 80.
    Schuler U, Ehninger G, Wagner T. Repeated high-dose cyclophosphamide administration in bone marrow transplantation: exposure to activated metabolites. Cancer Chemother Pharmacol 1987; 20: 248–52PubMedCrossRefGoogle Scholar
  81. 81.
    D’Incalci M, Bolis G, Facchinetti T, et al. Decreased half life of cyclophosphamide in patients under continual treatment. Eur J Cancer 1979; 13: 7–10Google Scholar
  82. 82.
    Chang TKH, Yu L, Maurel P, et al. Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res 1997; 57: 1946–54PubMedGoogle Scholar
  83. 83.
    Yule SM, Price L, Cole M, et al. Cyclophosphamide metabolism in children with Fanconi’s anaemia. Bone Marrow Transplant 1999; 24: 123–8PubMedCrossRefGoogle Scholar
  84. 84.
    Juma FD. Effect of liver failure on the pharmacokinetics of cyclophosphamide. Eur J Clin Pharmacol 1984; 26: 591–3PubMedCrossRefGoogle Scholar
  85. 85.
    Ren S, Kalhorn KF, McDonald GB, et al. Pharmacokinetics of cyclophosphamide and its metabolites in bone marrow transplantation patients. Clin Pharmacol Ther 1998; 64: 289–301PubMedCrossRefGoogle Scholar
  86. 86.
    Alberts DS, Mason-Liddil N, Plezia PM, et al. Lack of ranitidine effects on cyclophosphamide bone marrow toxicity or metabolism: a placebo-controlled clinical trial. J Natl Cancer Inst 1991; 83: 1739–43PubMedCrossRefGoogle Scholar
  87. 87.
    Faber OK, Mouridsen HT, Skovsted L. The biotransformation of cyclophosphamide in man: influence of prednisone. Acta Pharmacol Toxicol 1974; 35: 195–200CrossRefGoogle Scholar
  88. 88.
    Anderson L, Chen T-L, Colvin OM, et al. Cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide kinetics in patients receiving high-dose cyclophosphamide chemotherapy. Clin Cancer Res 1996; 2: 1481–7PubMedGoogle Scholar
  89. 89.
    Williams ML, Wainer IW, Embree L, et al. Enantioselective induction of cyclophosphamide metabolism by phenytoin. Chirality 1999; 11: 569–74PubMedCrossRefGoogle Scholar
  90. 90.
    Kennedy MJ, Zahurak ML, Donehower RC, et al. Sequence-dependent hematological toxicity associated with the 3-hour paclitaxel/cyclophosphamide doublet. Clin Cancer Res 1998; 4: 349–56PubMedGoogle Scholar
  91. 91.
    Holm KA, Kindberg CG, Stobaugh JF, et al. Stereoselective pharmacokinetics and metabolism of the enantiomers of cyclophosphamide. Preliminary results in humans and rabbits. Biochem Pharmacol 1990; 39: 1375–84PubMedCrossRefGoogle Scholar
  92. 92.
    Williams ML, Wainer TW, Granvil CP, et al. Pharmacokinetics of (R)- and (S)-cyclophosphamide and their dechloroethyl-ated metabolites in cancer patients. Chirality 1999; 11: 301–8PubMedCrossRefGoogle Scholar
  93. 93.
    Busse D, Busch FW, Schweizer E, et al. Fractionated administration of high-dose cyclophosphamide: influence on dosedependent changes in pharmacokinetics and metabolism. Cancer Chemother Pharmacol 1998; 43: 263–8CrossRefGoogle Scholar
  94. 94.
    Huitema ADR, Kerbusch T, Tibben MM, et al. Modelling of the pharmacokinetics (PK) and auto-induction of high-dose cyclophosphamide (CP) and 4-hydroxycyclophosphamide (HCP) using NONMEM [abstract 2536]. American Association for Cancer Research; 1999 Apr 10–14; Philadelphia, 40.Google Scholar
  95. 95.
    Ayash LJ, Wright JE, Tretyakov O, et al. Cyclophosphamide pharmacokinetics: Correlation with cardiac toxicity and tumor response. J Clin Oncol 1992; 10: 995–1000PubMedGoogle Scholar
  96. 96.
    Nieto Y, Xu XH, Cagnoni PJ, et al. Nonpredictable pharmacokinetic behavior of high-dose cyclophosphamide in combination with cisplatin and l,3-bis(2-chloroethyl)-l-nitrosurea. Clin Cancer Res 1999; 5: 747–51PubMedGoogle Scholar
  97. 97.
    Boddy AV, English M, Pearson ADJ, et al. Ifosfamide nephrotoxicity: limited influence of metabolism and mode of administration during repeated therapy in pediatrics. Eur J Cancer 1996; 32A: 1179–84.PubMedCrossRefGoogle Scholar
  98. 98.
    Boos J, Silies H, Hohenlochter B, et al. Short-term versus continuous infusion: no influence on ifosfamide side-chain metabolism. Eur J Cancer 1995; 31A: 2417–8PubMedCrossRefGoogle Scholar
  99. 99.
    Cerny T, Leyvraz T, von Briel A, et al. Saturable metabolism of continuous high dose ifosfamide with Mesna and GM-CSF: a pharmacokinetic study in advanced sarcoma patients. Ann Oncol 1999; 10: 1087–94PubMedCrossRefGoogle Scholar
  100. 100.
    Boddy AV, Idle JR. Combined thin-layer chromatography-photography-densitometry for the quantification of ifosfamide and its principal metabolites in urine, cerebrospinal fluid and plasma. J Chromatogr Biomed Appl 1992; 575: 137–42CrossRefGoogle Scholar
  101. 101.
    Boddy AV, Proctor M, Simmonds D, et al. Pharmacokinetics, metabolism and clinical effect of ifosfamide in breast cancer patients. Eur J Cancer 1995; 31A: 69–76PubMedCrossRefGoogle Scholar
  102. 102.
    Petros WP and Colvin OM. Metabolic jeopardy with high-dose cyclophosphamide?: not so fast. Clin Cancer Res 1999; 5: 723–4PubMedGoogle Scholar
  103. 103.
    Wainer IW, Ducharme J, Granvil CP, et al. Ifosfamide stereoselective dechloroethylation and neurotoxicity. Lancet 1994; 343: 982–3PubMedCrossRefGoogle Scholar
  104. 104.
    Cerny T, Margison JM, Thatcher N, et al. Bunavailability of ifosfamide in patients with bronchial carcinoma. Cancer Chemother Pharmacol 1986; 18: 261–4PubMedCrossRefGoogle Scholar
  105. 105.
    Wagner T, Drings P. Pharmacokinetics and bioavailability of oral ifosfamide. Arzniettelforschung 1986; 36: 878–80Google Scholar
  106. 106.
    Lind MJ, Margison JM, Cerny T, et al. Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma. Cancer Res 1989; 49: 753–7PubMedGoogle Scholar
  107. 107.
    Kurowski V, Cerny T, Kupfer A, et al. Metabolism and pharmacokinetics of oral and intravenous ifosfamide. J Cancer Res Clin Oncol 1991; 117 Suppl. 4: S148–S53.PubMedCrossRefGoogle Scholar
  108. 108.
    Aeschlimann C, Kupfer A, Schefer H, et al. Comparative pharmacokinetics of oral and intravenous ifosfamide/mesna/methylene blue therapy. Drug Metab Disp 1998; 26: 883–90Google Scholar
  109. 109.
    Lind MJ, Roberts HL, Thatcher N, et al. The effect of route of administration and fractionation of dose on the metabolism of ifosfamide. Cancer Chemother Pharmacol 1990; 26: 105–11PubMedCrossRefGoogle Scholar
  110. 110.
    Cerny T, Kupfer A. The enigma of ifosfamide encephalopathy. Ann Oncol 1992; 3: 679–81PubMedGoogle Scholar
  111. 111.
    Cerny T, Lind M, Thatcher N, et al. A simple outpatient treatment with oral ifosfamide and oral etoposide for patients with small cell lung cancer (SCLC). Br J Cancer 1989; 60: 258–61PubMedCrossRefGoogle Scholar
  112. 112.
    Lewis LD. A study of 5 day fractionated ifosfamide pharmacokinetics in consecutive treatment cycles. Br J Clin Pharmacol 1996; 42: 179–86PubMedCrossRefGoogle Scholar
  113. 113.
    Comandone A, Leone L, Oliva C, et al. Pharmacokinetics of ifosfamide administered according to three different schedules in metastatic solft tissue and bone sarcomas. J Chemotherapy 1998; 10: 385–93Google Scholar
  114. 114.
    Boddy AV, Yule SM, Wyllie R, et al. Comparison of continuous infusion and bolus administration of ifosfamide in children. Eur J Cancer 1995; 31A: 785–90PubMedCrossRefGoogle Scholar
  115. 115.
    Singer J, Hartley J, Brennan C, et al. The pharmacokinetics and metabolism of ifosfamide during bolus and infusional administration: a randomised cross-over study. Br J Cancer 1998; 77: 978–84PubMedCrossRefGoogle Scholar
  116. 116.
    Lind MJ, Margison JM, Cerny T, et al. Prolongation of ifosfamide elimination half-life in obese patients due to altered drug distribution. Cancer Chemother Pharmacol 1989; 25: 139–42PubMedCrossRefGoogle Scholar
  117. 117.
    Boddy AV, Yule SM, Wyllie R, et al. Pharmacokinetics and metabolism in children of ifosfamide administered as a continuous infusion. Cancer Res 1993; 53: 3758–64PubMedGoogle Scholar
  118. 118.
    Hartley JM, Hansen L, Harland SJ, et al. Metabolism of ifosfamide during a 3 day infusion. Br J Cancer 1994; 69: 931–6PubMedCrossRefGoogle Scholar
  119. 119.
    Corlett SA, Parker D, Chrystyn H. Pharmacokinetics of ifosfamide and its enantiomers following a single 1-h intravenous infusion of the racemate in patients with small-cell lung carcinoma. Br J Clin Pharmacol 1995; 39: 452–5PubMedCrossRefGoogle Scholar
  120. 120.
    Roy P, Tretyakov O, Wright J, et al. Stereoselective metabolism of ifosfamide by human P450s 3A4 and 2B6: favorable metabolic properties of the R-enantiomer. Drug Metab Disp 1999; 27: 1309–18Google Scholar
  121. 121.
    Walker D, Flinois J-P, Monkman SC, et al. Identification of the major human hepatic cytochrome P450 involved in activation and N-dechloroethylation of ifosfamide. Biochem Pharmacol 1994; 47: 1157–63PubMedCrossRefGoogle Scholar
  122. 122.
    Murray GI, McKay JA, Weaver RJ, et al. Cytochrome P450 expression is a common molecular event in soft tissue sarcomas. JPathol 1993; 171: 49–52CrossRefGoogle Scholar
  123. 123.
    Murray GI, Weaver RJ, Paterson PJ, et al. Expression of xenobiotic metabolizing enzymes in breast cancer. J Pathol 1993; 169: 347–53PubMedCrossRefGoogle Scholar
  124. 124.
    Janot F, Massaad L, Ribrag V, et al. Principal xenobiotic-metabolizing enzyme systems in human head and neck squamous cell carcinoma. Carcinogenesis 1993; 14: 1279–83PubMedCrossRefGoogle Scholar
  125. 125.
    Goren MP, Wright RK, Pratt CB, et al. Dechloroethylation of ifosfamide and neurotoxicity. Lancet 1986; II: 1219–20CrossRefGoogle Scholar
  126. 126.
    Kurowski V, Wagner T. Comparative pharmacokinetics of ifosfamide, 4-hydroxyifosfamide, chloroacetaldehyde and 2- and 3-dechloroethylifosfamide in patients on fractionated intravenous ifosfamide therapy. Cancer Chemother Pharmacol 1993; 33: 36–42PubMedCrossRefGoogle Scholar
  127. 127.
    Boddy AV, Cole M, Pearson ADJ, et al. The kinetics of the auto-induction of ifosfamide metabolism during continuous infusion. Cancer Chemother Pharmacol 1995; 36: 53–60PubMedCrossRefGoogle Scholar
  128. 128.
    Hassan M, Svensson U, Ljungman P, et al. A mechanism-based pharmacokinetic model for cyclophosphamide autoinduction in breast cancer patients. Br J Clin Pharmacol 1999; 48: 669–77PubMedCrossRefGoogle Scholar
  129. 129.
    Johnstone EC, Lind MJ, Siddiqui N, et al. Assessment of DNA damage caused by ifosfamide and metabolites [abstract 17].Google Scholar
  130. 130.
    Hartley JM, Spanswick VJ, Gander M, et al. Measurement of DNA cross-linking in patients on ifosfamide therapy using the single cell gel electrophoresis (comet) assay. Clin Cancer Res 1999; 5: 507–12PubMedGoogle Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  1. 1.Cancer Research Unit, Medical SchoolUniversity of Newcastle upon TyneEngland
  2. 2.The Royal Hospital for Sick ChildrenYorkhill, GlasgowScotland

Personalised recommendations