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.
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
Alarcon RA (1968) Fluorometric determination of acrolein and related compounds withm-aminophenol. Anal Chem 40: 1704–1708
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
Brade WP, Herdrich K, Varini M (1985) Ifosfamide — pharmacology, safety and therapeutic potential. Cancer Treat Rev 12: 1–47
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
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
Goren MP, Wright RK, Pratt CB, Pell FE (1986) Dechlorethylation of ifosfamide and neurotoxicity. Lancet II: 1219–1220
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
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
Lawrence WH, Dillingham EO, Turner JE, Autian J (1972) Toxicity profile of chloroacetaldehyde. J Pharm Sci 61: 19–25
Lewis LD, Meanwell CA (1990) Ifosfamide pharmacokinetics and neurotoxicity. Lancet 335: 175–176
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
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
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
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
Nelson RL, Allen JM, Creaven PJ (1976) Pharmacokinetics of divided dose ifosfamide. Clin Pharmacol Ther 19: 365–370
Norpoth K (1976) Studies on the metabolism of isophosphamide (NSC-109 724) in man. Cancer Treat Rep 60: 437–443
Piazza E, Cattaneo MT, Varini M (1984) Pharmacokinetic studies in lung cancer patients. Cancer 54: 1187–1192
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
Skinner R, Sharkey IM, Pearson AD, Craft AW (1993) Ifosfamide, mesna and nephrotoxicity in children. J Clin Oncol 11: 173–190
Sladek NE (1973) Bioassay and relative cytotoxic potency of cyclophosphamide metabolites generated in vitro and in vivo. Cancer Res 33: 1150–1158
Sladek NE (1988) Metabolism of oxazaphosphorines. Pharmacol Ther 37: 301–355
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
Wagner T, Drings P (1986) Pharmacokinetics and bioavailability of oral ifosfamide. Arzneimittelforschung 36: 878–880
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
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
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
Author information
Authors and Affiliations
Rights 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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00686020