Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1998 Mar;77(6):978–984. doi: 10.1038/bjc.1998.161

The pharmacokinetics and metabolism of ifosfamide during bolus and infusional administration: a randomized cross-over study.

J M Singer 1, J M Hartley 1, C Brennan 1, P W Nicholson 1, R L Souhami 1
PMCID: PMC2150089  PMID: 9528844

Abstract

In a randomized cross-over trial, 11 patients received ifosfamide (IFOS) in 21-day cycles, which alternated between 3 g m(-2) x (2 or 3) days given as a 1-h bolus doses, or the same total dose as a continuous infusion. Patients who received four or more cycles also alternated between two cycles on dexamethasone 4 mg 8 hourly for 3 days starting 8 h before IFOS, and two cycles off dexamethasone. A total of 34 patient cycles were studied and serum and urinary levels of IFOS, 2 dechloroethylifosfamide (2DC), 3 dechloroethylifosfamide (3DC), carboxyifosfamide (CX) and isophosphoramide mustard (IPM) were measured by thin-layer chromatography. No significant differences could be detected in the areas under the curve (AUCs) of serum concentration, nor in the proportion of IFOS or its metabolites found in the urine. There was no significant effect of dexamethasone on IFOS metabolism. These results indicate that there is no identifiable pharmacokinetic basis for insistence on either bolus or infusional methods of IFOS administration.

Full text

PDF
979

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen L. M., Creaven P. J. Human pharmacokinetic model for isophosphamide (NSC-1097241). Cancer Chemother Rep. 1975 Jul-Aug;59(4):877–882. [PubMed] [Google Scholar]
  2. Allen L. M., Creaven P. J. In vitro activation of isophosphamide (NSC-109724), a new oxazaphosphorine, by rat liver microsomes. Cancer Chemother Rep. 1972 Oct;56(5):603–610. [PubMed] [Google Scholar]
  3. Anderson H., Hopwood P., Prendiville J., Radford J. A., Thatcher N., Ashcroft L. A randomised study of bolus vs continuous pump infusion of ifosfamide and doxorubicin with oral etoposide for small cell lung cancer. Br J Cancer. 1993 Jun;67(6):1385–1390. doi: 10.1038/bjc.1993.256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. BROCK N., HOHORST H. J. UBER DIE AKTIVIERUNG VON CYCLOPHOSPHAMID IN VIVO UND IN VITRO. Arzneimittelforschung. 1963 Dec;13:1021–1031. [PubMed] [Google Scholar]
  5. Boddy A. V., Idle J. R. Combined thin-layer chromatography-photography-densitometry for the quantification of ifosfamide and its principal metabolites in urine, cerebrospinal fluid and plasma. J Chromatogr. 1992 Mar 13;575(1):137–142. doi: 10.1016/0378-4347(92)80514-q. [DOI] [PubMed] [Google Scholar]
  6. Boddy A. V., Yule S. M., Wyllie R., Price L., Pearson A. D., Idle J. R. Comparison of continuous infusion and bolus administration of ifosfamide in children. Eur J Cancer. 1995;31A(5):785–790. doi: 10.1016/0959-8049(95)00090-6. [DOI] [PubMed] [Google Scholar]
  7. Boddy A. V., Yule S. M., Wyllie R., Price L., Pearson A. D., Idle J. R. Intrasubject variation in children of ifosfamide pharmacokinetics and metabolism during repeated administration. Cancer Chemother Pharmacol. 1996;38(2):147–154. doi: 10.1007/s002800050463. [DOI] [PubMed] [Google Scholar]
  8. Boddy A. V., Yule S. M., Wyllie R., Price L., Pearson A. D., Idle J. R. Pharmacokinetics and metabolism of ifosfamide administered as a continuous infusion in children. Cancer Res. 1993 Aug 15;53(16):3758–3764. [PubMed] [Google Scholar]
  9. Brade W. P., Herdrich K., Varini M. Ifosfamide--pharmacology, safety and therapeutic potential. Cancer Treat Rev. 1985 Mar;12(1):1–47. doi: 10.1016/0305-7372(85)90011-8. [DOI] [PubMed] [Google Scholar]
  10. Brock N. The oxazaphosphorines. Cancer Treat Rev. 1983 Sep;10 (Suppl A):3–15. doi: 10.1016/s0305-7372(83)80002-4. [DOI] [PubMed] [Google Scholar]
  11. Creaven P. J., Allen L. M., Alford D. A., Cohen M. H. Clinical pharmacology of isophosphamide. Clin Pharmacol Ther. 1974 Jul;16(1):77–86. doi: 10.1002/cpt1974161part177. [DOI] [PubMed] [Google Scholar]
  12. Hartley J. M., Hansen L., Harland S. J., Nicholson P. W., Pasini F., Souhami R. L. Metabolism of ifosfamide during a 3 day infusion. Br J Cancer. 1994 May;69(5):931–936. doi: 10.1038/bjc.1994.180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kaijser G. P., Beijnen J. H., Bult A., Underberg W. J. Ifosfamide metabolism and pharmacokinetics (review). Anticancer Res. 1994 Mar-Apr;14(2A):517–531. [PubMed] [Google Scholar]
  14. Kaijser G. P., Korst A., Beijnen J. H., Bult A., Underberg W. J. The analysis of ifosfamide and its metabolites (review). Anticancer Res. 1993 Sep-Oct;13(5A):1311–1324. [PubMed] [Google Scholar]
  15. Klein H. O., Wickramanayake P. D., Christian E., Coerper C. Therapeutic effects of single-push or fractionated injections or continuous infusion of oxazaphosphorines (cyclophosphamide, ifosfamide, Asta Z 7557). Cancer. 1984 Sep 15;54(6 Suppl):1193–1203. doi: 10.1002/1097-0142(19840915)54:1+<1193::aid-cncr2820541317>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  16. Lind M. J., Margison J. M., Cerny T., Thatcher N., Wilkinson P. M. Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma. Cancer Res. 1989 Feb 1;49(3):753–757. [PubMed] [Google Scholar]
  17. Lind M. J., Margison J. M., Cerny T., Thatcher N., Wilkinson P. M. Prolongation of ifosfamide elimination half-life in obese patients due to altered drug distribution. Cancer Chemother Pharmacol. 1989;25(2):139–142. doi: 10.1007/BF00692355. [DOI] [PubMed] [Google Scholar]
  18. Lind M. J., Roberts H. L., Thatcher N., Idle J. R. The effect of route of administration and fractionation of dose on the metabolism of ifosfamide. Cancer Chemother Pharmacol. 1990;26(2):105–111. doi: 10.1007/BF02897254. [DOI] [PubMed] [Google Scholar]
  19. Morgan L. R., Harrison E. F., Hawke J. E., Hunter H. L., Costanzi J. J., Plotkin D., Tucker W. G., Worrall P. M. Toxicity of single- vs. fractionated-dose ifosfamide in non-small cell lung cancer: a multi-center study. Semin Oncol. 1982 Dec;9(4 Suppl 1):66–70. [PubMed] [Google Scholar]
  20. Murray M., Butler A. M., Stupans I. Competitive inhibition of human liver microsomal cytochrome P450 3A-dependent steroid 6 beta-hydroxylation activity by cyclophosphamide and ifosfamide in vitro. J Pharmacol Exp Ther. 1994 Aug;270(2):645–649. [PubMed] [Google Scholar]
  21. Nelson R. L., Allen L. M., Creaven P. J. Pharmacokinetics of divided-dose ifosfamide. Clin Pharmacol Ther. 1976 Mar;19(3):365–370. doi: 10.1002/cpt1976193365. [DOI] [PubMed] [Google Scholar]
  22. Rodriguez V., Bodey G. P., Freireich E. J., McCredie K. B., McKelvey E. M., Tashima C. K. Reduction of ifosfamide toxicity using dose fractionation. Cancer Res. 1976 Aug;36(8):2945–2948. [PubMed] [Google Scholar]
  23. Ruzicka J. A., Ruenitz P. C. Cytochrome P-450-mediated N-dechloroethylation of cyclophosphamide and ifosfamide in the rat. Drug Metab Dispos. 1992 Sep-Oct;20(5):770–772. [PubMed] [Google Scholar]
  24. Wagner T. Ifosfamide clinical pharmacokinetics. Clin Pharmacokinet. 1994 Jun;26(6):439–456. doi: 10.2165/00003088-199426060-00003. [DOI] [PubMed] [Google Scholar]
  25. Walker D., Flinois J. P., Monkman S. C., Beloc C., Boddy A. V., Cholerton S., Daly A. K., Lind M. J., Pearson A. D., Beaune P. H. Identification of the major human hepatic cytochrome P450 involved in activation and N-dechloroethylation of ifosfamide. Biochem Pharmacol. 1994 Mar 29;47(7):1157–1163. doi: 10.1016/0006-2952(94)90387-5. [DOI] [PubMed] [Google Scholar]
  26. Weber G. F., Waxman D. J. Activation of the anti-cancer drug ifosphamide by rat liver microsomal P450 enzymes. Biochem Pharmacol. 1993 Apr 22;45(8):1685–1694. doi: 10.1016/0006-2952(93)90310-s. [DOI] [PubMed] [Google Scholar]
  27. Yule S. M., Boddy A. V., Cole M., Price L., Wyllie R., Tasso M. J., Pearson A. D., Idle J. R. Cyclophosphamide metabolism in children. Cancer Res. 1995 Feb 15;55(4):803–809. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES