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. 1994 May;69(5):931–936. doi: 10.1038/bjc.1994.180

Metabolism of ifosfamide during a 3 day infusion.

J M Hartley 1, L Hansen 1, S J Harland 1, P W Nicholson 1, F Pasini 1, R L Souhami 1
PMCID: PMC1968912  PMID: 8180026

Abstract

Urinary drug metabolites were measured in 21 patients receiving ifosfamide by continuous infusion over 3 days. Mean values for the proportion of drug excreted as parent compound, 2-dechloroethylifosfamide (2-DC), 3-dechloroethylifosfamide (3-DC), carboxyifosfamide (CX) and ifosforamide mustard (IPM) were 19, 6, 10, 7 and 8% of dose respectively. The proportion of urinary drug products in the form of ifosfamide fell considerably over the course of the 3 days. This was mirrored by an increase in the proportion of 2-DC, 3-DC and CX. The proportion in the form of IPM, however, remained unchanged. With successive cycles the amount of 2-DC and IPM increased by about 10% per course. A very wide variation in the amount of each metabolite was reproducibly seen between patients, but no evidence for a genetic polymorphism was found. Urinary dechloroethyl metabolites correlated positively with each other and negatively with CX. Although autoinduction increases 'activation' of ifosfamide when given over 3 days, our evidence suggests that competing metabolic pathways prevent an increase in the amount of active metabolite formed.

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Selected References

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  1. Alarcon R. A., Meienhofer J., Atherton E. Isophosphamide as a new acrolein-producing antineoplastic isomer of cyclophosphamide. Cancer Res. 1972 Nov;32(11):2519–2523. [PubMed] [Google Scholar]
  2. 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]
  3. 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]
  4. Brock N., Pohl J., Stekar J. Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention. 2. Comparative study on the uroprotective efficacy of thiols and other sulfur compounds. Eur J Cancer Clin Oncol. 1981 Nov;17(11):1155–1163. [PubMed] [Google Scholar]
  5. Cockcroft D. W., Gault M. H. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41. doi: 10.1159/000180580. [DOI] [PubMed] [Google Scholar]
  6. Connors T. A., Cox P. J., Farmer P. B., Foster A. B., Jarman M. Some studies of the active intermediates formed in the microsomal metabolism of cyclophosphamide and isophosphamide. Biochem Pharmacol. 1974 Jan 1;23(1):115–129. doi: 10.1016/0006-2952(74)90318-9. [DOI] [PubMed] [Google Scholar]
  7. Goren M. P., Wright R. K., Pratt C. B., Pell F. E. Dechloroethylation of ifosfamide and neurotoxicity. Lancet. 1986 Nov 22;2(8517):1219–1220. doi: 10.1016/s0140-6736(86)92227-0. [DOI] [PubMed] [Google Scholar]
  8. Hadidi A. H., Coulter C. E., Idle J. R. Phenotypically deficient urinary elimination of carboxyphosphamide after cyclophosphamide administration to cancer patients. Cancer Res. 1988 Sep 15;48(18):5167–5171. [PubMed] [Google Scholar]
  9. Lewis L. D., Fitzgerald D. L., Harper P. G., Rogers H. J. Fractionated ifosfamide therapy produces a time-dependent increase in ifosfamide metabolism. Br J Clin Pharmacol. 1990 Nov;30(5):725–732. doi: 10.1111/j.1365-2125.1990.tb03842.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Malet-Martino M. C., Martino R. Magnetic resonance spectroscopy: a powerful tool for drug metabolism studies. Biochimie. 1992 Sep-Oct;74(9-10):785–800. doi: 10.1016/0300-9084(92)90061-i. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Norpoth K. Studies on the metabolism of isopnosphamide (NSC-109724) in man. Cancer Treat Rep. 1976 Apr;60(4):437–443. [PubMed] [Google Scholar]
  15. Piazza E., Cattaneo M. T., Varini M. Pharmacokinetic studies in lung cancer patients. Cancer. 1984 Sep 15;54(6 Suppl):1187–1192. doi: 10.1002/1097-0142(19840915)54:1+<1187::aid-cncr2820541316>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  16. Skinner R., Sharkey I. M., Pearson A. D., Craft A. W. Ifosfamide, mesna, and nephrotoxicity in children. J Clin Oncol. 1993 Jan;11(1):173–190. doi: 10.1200/JCO.1993.11.1.173. [DOI] [PubMed] [Google Scholar]
  17. Sladek N. E. Metabolism of oxazaphosphorines. Pharmacol Ther. 1988;37(3):301–355. doi: 10.1016/0163-7258(88)90004-6. [DOI] [PubMed] [Google Scholar]
  18. Wagner T., Drings P. Pharmacokinetics and bioavailability of oral ifosfamide. Arzneimittelforschung. 1986 May;36(5):878–880. [PubMed] [Google Scholar]

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