Metabolism and pharmacokinetics of oxazaphosphorines

Clinical Pharmacokinetics

Volumn 38, Issue 4, 2000, Pages 291-304

  Boddy, Alan V ^a,b   Yule, S Murray ^a,b  

^a NEWCASTLE UNIVERSITY   (United Kingdom)

^b ROYAL HOSPITAL FOR SICK CHILDREN   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALLOPURINOL; ANTICONVULSIVE AGENT; ANTIFUNGAL AGENT; CARBAMAZEPINE; CHLORAMPHENICOL; CHLORPROMAZINE; CYCLOPHOSPHAMIDE; CYTOCHROME P450 ISOENZYME; DEXAMETHASONE; FLUCONAZOLE; IFOSFAMIDE; KETOCONAZOLE; OXAZAPHOSPHORINE DERIVATIVE; PACLITAXEL; PHENOBARBITAL; PHENYTOIN; PREDNISOLONE; RANITIDINE; THIOTEPA;

ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CYTOTOXICITY; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG EXCRETION; DRUG HALF LIFE; DRUG HYDROXYLATION; DRUG INACTIVATION; DRUG MECHANISM; DRUG METABOLISM; DRUG RESISTANCE; HUMAN; MATHEMATICAL MODEL; NEUROTOXICITY; PHARMACODYNAMICS; PRIORITY JOURNAL; REVIEW; STEREOCHEMISTRY;

ANIMALS; ANTINEOPLASTIC AGENTS, ALKYLATING; CYCLOPHOSPHAMIDE; DRUG INTERACTIONS; HUMANS; IFOSFAMIDE;

EID: 0034053590     PISSN: 03125963     EISSN: None     Source Type: Journal    
DOI: 10.2165/00003088-200038040-00001     Document Type: Review

References (130)

1. Brock N. Oxazaphosphorine cytostatics: past-present-future.Cancer Res 1989; 49: 1-7
2. Colvin M. The comparative pharmacology of cyclophosphamide and ifosfamide. Semin Oncol 1982; 9: 2-7
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 Immunopharmacol 1986; 8: 455-80
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: 419-31
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: 58-65
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 SAATI. Proc Natl Acad Sci U S A 1998; 95: 2914-9
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: 6168-74
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: 2366-71
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: 327-34
10. Moore MJ. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 1991; 20: 194-208
11. Kaijser GP, Beijnen JH, Bult A, et al. Ifosfamide metabolism and pharmacokinetics [review]. Anticancer Res 1994; 14: 517-32
12. Wagner T. Ifosfamide clinical pharmacokinetics. Clin Pharmacokinet 1994; 26: 439-56
13. Fleming RA. An overview of cyclophosphamide and ifosfamide pharmacology. Pharmacotherapy 1997; 5 (Pt 2): S146-54
14. Kohn KW, Hartley JA, Mattes WB. Mechanisms of DNA sequence alkylation of guanine-N7 positions by nitrogen mustards. Nucl Acid Res 1987; 14: 10531-45
15. Springer JB, Colvin ME, Colvin OM, et al. Isophosphoramide mustard and its mechanism of bisalkylation. J Org Chem 1998; 63: 7218-22
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: 515-29
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: 6550-7
18. Hickman JA. Apoptosis and cancer chemotherapy. Cancer Metastasis Rev 1992; 11: 121-39
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: 5035-8
20. Richardson ME, Siemann DW. DNA damage in cyclophosphamide-resistant tumor cells: the role of glutathione. Cancer Res 1995; 55: 1691-5
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: 5394-400
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: 242-6
23. Maki PA, Sladek NE. Sensitivity of aldehyde dehydrogenases in murine tumor and hematopoietic progenitor cells to inhibition hy chloral hydrate to potentiate the cytotoxic action of mafosfamide. Biochem Pharmacol 1993; 45: 231-9
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: 2487-505
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: 617-20
26. Magni M, Shammah S, Schiro R, et al. Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. Blood 1996; 87: 1097-103
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: 2576-82
28. Friedman HS, Pegg AE, Johnson SP, et al. Modulation of cyclophosphamide activity by O-6-alkylguanine-DNA alkyltransferase. Cancer Chemother Pharmacol 1999; 43: 80-5
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: 901-6
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: 1858-69
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: 1732-9
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: 3122-33
33. Frei E, Teicher BA, Holden SA, et al. Preclinical studies and clinical correlation of the effect of alkylating dose. Cancer Res 1988; 48: 6417-23
34. Teicher BA, Cucchi CA, Lee JB, et al. In vitro studies of cross-resistance patterns in human cell lines. Cancer Res 1986; 46: 4379-83
35. Lilley ER, Rosenberg MC, Elion GB, et al. Synergistic interactions between cyclophosphamide or melphalan and VP-16 in a human rhabdomyosarcoma xenograft. Cancer Res 1990; 15: 284-7
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: 1838-46
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: 1193-203
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: 229-31
39. Jardine I, Fenselau C, Appler 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: 408-15
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: 3730-5
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: 149-58
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: 393-8
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: 275-84
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: 1484-94
45. Baumann F, Lorenz C, Jaehde U, et al. Determination of cyclophosphamide and its metabolites in human plasma by high-performance liquid chromatography-mass spectrometry. J Chromatogr B 1999; 729: 297-305
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: 391-9
47. Reid JM, Stobaugh JF, Sternson LA. Liquid chromatographic determination of cyclophosphamide enantiomers in plasma by precolumn chiral derivatization. Anal Chem 1989; 61: 441-6
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: 133-43
49. Struck RF, Alberts DS, Horne K, et al. Plasma pharmacokinetics of cyclophosphamide and its cytotoxic metabolites after intravenous versus oral administration in a randomized, cross-over trial. Cancer Res 1987; 47: 2732-26
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: 209-17
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: 200-6
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: 459-64
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: 219-22
54. Hommes 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: 297-303
55. Neuwelt EA, Barnett PA, Frenkel EP. 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: 154-60
56. Yule SM, Price L, Pearson ADJ, et al. Cyclophosphamide and ifosfamidE metabolites in the cerebrospinal fluid of children. Clin Cancer Res 1997; 3: 1985-92
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: 382-8
58. Fasola G, Lo Greco P, Calori E, et al. Pharmacokinetics of high-dose cyclophosphamide for bone marrow transplantation. Haematologica 1991; 76: 120-5
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: 1099-104
60. Dooley JS, James CA, Rogers HJ, et al. Biliary elimination of cyclophosphamide in man. Cancer Chemother Pharmacol 1982; 9: 26-9
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: 1436-41
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: 581-9
63. Sladek N. Metabolism of oxazaphosphorines. Pharmacol Ther 1988; 37: 301-55
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: 5629-37
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: 2538-43
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: 2453-69
67. Bohnenstengel E, 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: 297-301
68. Ren S, Yang JS, Kalhorn TF, et al. Oxidation of cyclophosphamide to 4-hydroxycyclophosphamide and deschloroethylcyclophosphamide in human liver microsomes. Cancer Res 1997; 57: 4229-35
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: 1744-8
70. Hadidi A-HFA, Coulter CEA, Idle JR. Phenotypically deficient urinary elimination of carboxyphosphamide after cyclophosphamide administration to cancer patients. Cancer Res 1988; 48: 5167-71
71. Yule SM, Boddy AV, Cole M, et al. Cyclophosphamide metabolism in children. Cancer Res 1995; 55: 803-9
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: 655-66
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: 472-6
74. Yule SM, Boddy AV, Cole M, et al. Cyclophosphamide pharmacokinetics in children. Br J Clin Pharmacol 1996; 41: 13-9
75. Yule SM, Walker D, Cole M, et al. The effect of fluconazole on cyclophosphamide metabolism in children. Drug Metab Disp 1999; 27: 417-21
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: 810-6
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: 1885-96
78. Bramwell V, Calvert RT, Edwards G, et al. The disposition of cyclophosphamide in a group of myeloma patients. Cancer Chemother Pharmacol 1979; 3: 253-9
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: 443-51
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: 248-52
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: 7-10
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: 1946-54
83. Yule SM, Price L, Cole M, et al. Cyclophosphamide metabolism in children with Fanconi's anaemia. Bone Marrow Transplant 1999; 24: 123-8
84. Juma FD. Effect of liver failure on the pharmacokinetics of cyclophosphamide. Eur J Clin Pharmacol 1984; 26: 591-3
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: 289-301
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: 1739-43
87. Faber OK, Mouridsen HT, Skovsted L. The biotransformation of cyclophosphamide in man: influence of prednisone. Acta Pharmacol Toxicol 1974; 35: 195-200
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: 1481-7
89. Williams ML, Wainer IW, Embree L, et al. Enantioselective induction of cyclophosphamide metabolism by phenytoin. Chirality 1999; 11: 569-74
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: 349-56
91. Holm KA, Kindberg CG, Stohaugh JF, et al. Stereoselective pharmacokinetics and metabolism of the enantiomers of cyclophosphamide. Preliminary results in humans and rabbits. Biochem Pharmacol 1990; 39: 1375-84
92. Williams ML, Wainer IW, Granvil CP, et al. Pharmacokinetics of (R)-and (S)-cyclophosphamide and their dechloroethylated metabolites in cancer patients. Chirality 1999; 11: 301-8
93. Busse D, Busch FW, Schweizer E, et al. Fractionated administration of high-dose cyclophosphamide: influence on dose-dependent changes in pharmacokinetics and metabolism. Cancer Chemother Pharmacol 1998; 43: 263-8
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
95. Ayash LJ, Wright JE, Tretyakov O, et al. Cyclophosphamide pharmacokinetics: Correlation with cardiac toxicity and tumor response. J Clin Oncol 1992; 10: 995-1000
96. Nieto Y, Xu XH, Cagnoni PJ, et al. Nonpredictable pharmacokinetic behavior of high-dose cyclophosphamide in combination with cisplatin and 1,3-bis(2-chloroethyl)-1-nitrosurea. Clin Cancer Res 1999; 5: 747-51
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
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: 2417-8
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: 1087-94
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: 137-42
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: 69-76
102. Petros WP and Colvin OM. Metabolic jeopardy with high-dose cyclophosphamide?: not so fast. Clin Cancer Res 1999; 5: 723-4
103. Wainer IW, Ducharme J, Granvil CP, et al. Ifosfamide stereoselective dechloroethylation and neurotoxicity. Lancet 1994; 343: 982-3
104. Cerny T, Margison JM, Thatcher N, et al. Bioavailability of ifosfamide in patients with bronchial carcinoma. Cancer Chemother Pharmacol 1986; 18: 261-4
105. Wagner T, Drings P. Pharmacokinetics and bioavailability of oral ifosfamide. Arzniettelforschung 1986; 36: 878-80
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: 753-7
107. Kurowski V, Cerny T, Küpfer A, et al. Metabolism and pharmacokinetics of oral and intravenous ifosfamide. J Cancer Res Clin Oncol 1991; 117 Suppl. 4: S148-S53
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: 883-90
109. Lind MJ, Roberts HL, Thatcher N, et al. The effect of route of administration and tractionation of dose on the metabolism of ifosfamide. Cancer Chemother Pharmacol 1990; 26: 105-11
110. Cerny T, Küpfer A. The enigma of ifosfamide encephalopathy. Ann Oncol 1992; 3: 679-81
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: 258-61
112. Lewis LD. A study of 5 day fractionated ifosfamide pharmacokinetics in consecutive treatment cycles. Br J Clin Pharmacol 1996; 42: 179-86
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: 385-93
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: 785-90
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: 978-84
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: 139-42
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: 3758-64
118. Hartley JM, Hansen L, Harland SJ, et al. Metabolism of ifosfamide during a 3 day infusion. Br J Cancer 1994; 69: 931-6
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: 452-5
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: 1309-18
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: 1157-63
122. Murray GI, McKay JA, Weaver RJ, et al. Cytochrome P450 expression is a common molecular event in soft tissue sarcomas. J Pathol 1993; 171: 49-52
123. Murray GI, Weaver RJ, Paterson PJ, et al. Expression of xenobiotic metabolizing enzymes in breast cancer. J Pathol 1993; 169: 347-53
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: 1279-83
125. Goren MP, Wright RK, Pratt CB, et al. Dechloroethylation of ifosfamide and neurotoxicity. Lancet 1986; 11: 1219-20
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: 36-42
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: 53-60
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: 669-77
129. Johnstone EC, Lind MJ, Siddiqui N, et al. Assessment of DNA damage caused by ifosfamide and metabolites [abstract 17]. Annual Conference of the American Association for Cancer Research; 1997 Apr 12-16; San Diego, 38: 3
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: 507-12