Skip to main content
Log in

Comparative pharmacokinetics of ifosfamide, 4-hydroxyifosfamide, chloroacetaldehyde, and 2- and 3-dechloroethylifosfamide in patients on fractionated intravenous ifosfamide therapy

  • Original Articles
  • Ifosfamide, Fractionated Therapy, Metabolism, Auto-Induction, Pharmacokinetics
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

The initial metabolism of the oxazaphosphorine cytostatic ifosfamide (IF) consists of two different pathways: ring oxidation at carbon-4 forms the cytostatically active metabolite 4-hydroxyifosfamide (4-OH-IF, “activated ifosfamide”), whereas side-chain oxidation with liberation of the presumably neurotoxic compound chloroacetaldehyde (CAA) that may also be responsible for IF-associated nephrotoxicity results in the formation of the cytostatically inactive metabolites 2-dechloroethylifosfamide (2-DCE-IF) and 3-dechloroethylifosfamide (3-DCE-IF). The pharmacokinetics of IF and its metabolites were investigated in 11 patients with bronchogenic carcinoma receiving IF on a 5-day divided-dose schedule (1.5 g/m2 daily). Blood samples were drawn on days 1 and 5 for up to 24 h after the start of the IF infusion. IF, 2-DCE-IF, and 3-DCE-IF were simultaneously quantified by gas chromatography (GC) with an NIP flame-ionization detector (NPFID), CAA was determined by GC with an electron-capture detector (ECD), and the highly unstable compound 4-OH-IF was measured using a high-performance liquid chromatography (HPLC) assay with fluorometric detection of 7-OH-quinoline, which is formed by the condensation of 4-OH-IF-derived acrolein withm-aminophenol. As compared with the values obtained on day 1, on day 5 the terminal half-life and AUC values determined for IF were reduced by 30% (6.36 vs 4.06 h and 1781 vs 1204 nmol h ml−1, respectively), whereas the maximal concentration (Cmax) values were not affected significantly (199.1 vs 181.1 nmol ml−1). This known phenomenon is explained by autoinduction of hepatic IF metabolism and was paralleled by increased metabolite levels. The mean Cmax values determined for 4-OH-IF, CAA, 3-DCE-IF, and 2-DCE-IF (on day 1/on day 5) were 1.51/2.59, 2.69/4.85, 12.9/26.5, and 8.6/16.7 nmol ml−1, respectively. The corresponding AUC values were 11.3/16.5, 30.3/34.3, 146/354, and 111/209 nmol h ml−1, respectively. As calculated by intraindividual comparison, the mean Cmax (day 5)∶Cmax (day 1) ratios for 4-OH-IF, CAA, 3-DCE-IF, and 2-DCE-IF were 1.94*, 2.05*, 2.52*, and 2.33*, respectively; the corresponding AUC (day 5)∶AUC (day 1) ratios were 1.51*, 1.29, 2.34*, and 2.23*, respectively (* P<0.05). These data reveal that during fractionated-dose IF therapy the cancerotoxic effect of the drug increases. If the assumed role of CAA in IF-associated neurotoxicity and nephrotoxicity is a dose-dependent phenomenon, the probability of developing these side effects would also increase during prolonged IF application.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

IF:

ifosfamide

CAA:

chloroacetaldehyde

CP:

cyclophosphamide

4-OH-IF:

4-hydroxyifosfamide (“activated ifosfamide”)

2-DCE-IF:

2-dechloroethylifosfamide

3-DCE-IF:

3-dechloroethylifosfamide

References

  1. Alarcon RA (1968) Fluorometric determination of acrolein and related compounds withm-aminophenol. Anal Chem 40: 1704–1708

    Google Scholar 

  2. Boos J, Welslau U, Ritter J, Blaschke G, Schellong G (1991) Urinary excretion of the enantiomers of ifosfamide and its inactive metabolites in children. Cancer Chemother Pharmacol 28: 455–460

    Google Scholar 

  3. Brade WP, Herdrich K, Varini M (1985) Ifosfamide — pharmacology, safety and therapeutic potential. Cancer Treat Rev 12: 1–47

    Google Scholar 

  4. Connors TA, Cox PJ, Farmer PB, Foster AB, Jarman M (1973) Some studies of the active intermediates formed in the microsomal metabolism of cyclophosphamide and isophosphamide. Biochem Pharmacol 23: 115–129

    Google Scholar 

  5. Drings P, Abel U, Bülzebruck H, Stiefel P, Kleckow M, Manke HG (1986) Experience with ifosfamide combinations (etoposide or DDP) in non small cell lung cancer. Cancer Chemother Pharmacol 18 [Suppl 2]: 34–39

    Google Scholar 

  6. Goren MP, Wright RK, Pratt CB, Pell FE (1986) Dechlorethylation of ifosfamide and neurotoxicity. Lancet II: 1219–1220

    Google Scholar 

  7. Klein HO, Wickramanayake PD, Christian E, Coerper C (1984) Therapeutic effects of single-push or fractionated injections or continuous infusion of oxazaphosphorines (cyclophosphamide, ifosfamide, ASTA Z 7557). Cancer 54: 1193–1203

    Google Scholar 

  8. Kurowski V, Cerny T, Küpfer A, Wagner T (1991) Metabolism and pharmacokinetics of oral and intravenous ifosfamide. J Cancer Res Clin Oncol 117 [Suppl IV]: S148-S153

    Google Scholar 

  9. Lawrence WH, Dillingham EO, Turner JE, Autian J (1972) Toxicity profile of chloroacetaldehyde. J Pharm Sci 61: 19–25

    Google Scholar 

  10. Lewis LD, Meanwell CA (1990) Ifosfamide pharmacokinetics and neurotoxicity. Lancet 335: 175–176

    Google Scholar 

  11. Lewis LD, Fitzgerald DL, Harper PG, Rogers HJ (1990) Fractionated ifosfamide therapy produces a time-dependent increase in ifosfamide metabolism. Br J Clin Pharmacol 30: 725–732

    Google Scholar 

  12. Lind MJ, Margison JM, Cerny T, Thatcher N, Wilkinson PM (1989) Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma. Cancer Res 49: 753–757

    Google Scholar 

  13. Lind MJ, Roberts HL, Thatcher N, Idle JR (1990) The effect of route of administration and fractionation of dose on the metabolism of ifosfamide. Cancer Chemother Pharmacol 26: 105–111

    Google Scholar 

  14. Morgan LR, Harrison EF, Hawke JE, Hunter HL, Costanzi JJ, Plotkin D, Tucker WG, Worall PM (1982) Toxicity of single- vs fractionated-dose ifosfamide in non small cell lung cancer: a multicenter study. Semin Oncol [Suppl 1]: 66–70

    Google Scholar 

  15. Nelson RL, Allen JM, Creaven PJ (1976) Pharmacokinetics of divided dose ifosfamide. Clin Pharmacol Ther 19: 365–370

    Google Scholar 

  16. Norpoth K (1976) Studies on the metabolism of isophosphamide (NSC-109 724) in man. Cancer Treat Rep 60: 437–443

    Google Scholar 

  17. Piazza E, Cattaneo MT, Varini M (1984) Pharmacokinetic studies in lung cancer patients. Cancer 54: 1187–1192

    Google Scholar 

  18. Schuler U, Ehninger G, Wagner T (1987) Repeated high-dose cyclophosphamide administration in bone marrow transplantation: exposure to activated metabolites. Cancer Chemother Pharmacol 20: 248–252

    Google Scholar 

  19. Skinner R, Sharkey IM, Pearson AD, Craft AW (1993) Ifosfamide, mesna and nephrotoxicity in children. J Clin Oncol 11: 173–190

    Google Scholar 

  20. Sladek NE (1973) Bioassay and relative cytotoxic potency of cyclophosphamide metabolites generated in vitro and in vivo. Cancer Res 33: 1150–1158

    Google Scholar 

  21. Sladek NE (1988) Metabolism of oxazaphosphorines. Pharmacol Ther 37: 301–355

    Google Scholar 

  22. Sladek NE, Doeden P, Powers JF, Krivit W (1984) Plasma concentrations of 4-hydroxy-cyclophosphamide and phosphoramide mustard in patients repeatedly given high doses of cyclophosphamide in preparation for bone marrow transplantation. Cancer Treat Rep 68: 1247–1254

    Google Scholar 

  23. Wagner T, Drings P (1986) Pharmacokinetics and bioavailability of oral ifosfamide. Arzneimittelforschung 36: 878–880

    Google Scholar 

  24. Wagner T, Peter G, Voelcker G, Hohorst HJ (1977) Characterization and quantitative estimation of activated cyclophosphamide in blood and urine. Cancer Res 37: 2592–2596

    Google Scholar 

  25. Wagner T, Heydrich D, Jork T, Voelcker G, Hohorst HJ (1981) Comparative study on human pharmacokinetics of activated ifosfamide and cyclophosphamide by a modified fluorometric test. J Cancer Res Clin Oncol 100: 95–104

    Google Scholar 

  26. Wolf M, Havemann K, Holle R, Gropp C, Drings P, Hans K, Schröder M, Heim M (1987) Cisplatin/etoposide versus ifosfamide/etoposide combination chemotherapy in small-cell lung cancer: a multicenter German randomized trial. J Clin Oncol 5: 1880–1889

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

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. 33, 36–42 (1993). https://doi.org/10.1007/BF00686020

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00686020

Keywords

Navigation