Summary
The activated metabolites of ifosfamide and cyclophosphamide (4-hydroxy-ifosfamide and 4-hydroxy-cyclophosphamide) were analysed fluorometrically by condensation of liberated acrolein with m-aminophenol yielding 7-hydroxychinolin. Interfering fluorescence of blood and urine was eliminated by extraction with dichlormethane and determination of blanks in which the liberated acrolein reacted with hydrazine to non-fluorescent pyrazoline. The modified test proved effective in identifying low levels of activated metabolites in man. After i.v. injection of 20 mg/kg cyclophosphamide or ifosfamide peak levels of activated cyclophosphamide (4.7 nmol/ml) and the area under the curve (c·t=16.7 nmol·ml/h) showed mean values three times higher than those found for activated ifosfamide.
One per cent of the applied dosis of cyclophosphamide vs. 0.3% of ifosfamide was excreted as activated metabolites. Due to the high stability of activated cyclophosphamide and ifosfamide in urine a low liberation rate of acrolein was found, the concentration of which in urine was below 0.5 nmol/ml. Acrolein, which was directly liberated from activated cyclophosphamide or ifosfamide, does not seem to play an important role in the urotoxicity of these cytostatics.
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References
Alarcon RA (1968) Fluorometric determination of acrolein and related compounds with m-aminophenol. Anal Chem 40:1704–1708
Allen LM, Creaven PJ, Nelson RL (1976) Studies on the human pharmacokinetics of isophosphamide (NSC-109724). Cancer Treatm Rep 60:451–458
Brock N (1976) Comparative pharmacologic study in vitro and in vivo with cyclophosphamide (NSC-26271), cyclophosphamide metabolites, and plain nitrogen mustard compounds. Cancer Treatm Rep 60:301–308
Brock N, Hohorst HJ (1977) The problem of specificity and selectivity of alkylating cytostatics: studies on N-2-chloro-ethylamido-oxazaphosphorines. Z Krebsforsch 88:185–215
Brock N, Stekar J, Pohl J, Niemyer U, Scheffler G (1979) Acrolein, the causative factor of urotoxic side-effects of cyclophosphamide, ifosfamide, trofosfamide, and sufosfamide. Arzneim Forsch 29:659–661
Cox PJ (1979) Cyclophosphamide cystitis, identification of acrolein as the causative agent. Biochem Pharmac 28:2045–2049
Creaven PJ, Allen LM, Cohen MH, Nelson RL (1976) Studies on the clinical pharmacology and toxicology of isophosphamide (NSC-109724). Cancer Treatm Rep 60:445–449
Dräger U, Peter G, Hohorst HJ (1976) Deactivation of cyclophosphamide (NSC-26271) metabolites by sulfhydryl compounds. Cancer Treatm Rep 60:355–359
Däger U, Hohorst HJ (1976) Permeation of cyclophosphamide (NSC-26271) metabolites into tumor cells. Cancer Treatm Rep 60:432–427
Fenselau C, Kan MNN, Rao SS, Myles A, Friedman OM, Colvin M (1977) Identification of aldophosphamide as a metabolite of cyclophosphamide in vitro and in vivo in humans. Cancer Res 37:2538–2543
Friedman OM, Myles A, Colvin M (1979) Cyclophosphamide and related phosphoramid mustards. Advances in Cancer Chemotherapy. A. Rosowsky, Boston (Mass)
Hohorst HJ, Peter G, Struck RF (1976 a) 4-Hydroperoxy Derivatives of ifosfamide and trofosfamide: Synthesis by direct ozonation and antitumor evaluation in vivo. Cancer Res 36:2278–2283
Hohorst HJ, Dräger U, Peter G, Voelcker G (1976 b) The problem of oncostatic specificity of cyclophosphamide (NSC-26271): Studies on reactions that control the alkylating and cytotoxic activity. Cancer Treatm Rep 60:309–315
Mellet JB, El Dareer SM, Luce JK, Frei E (1969) III. Activation and cyclophosphamide metabolism in various species. Pharmacologist 11:273
Norpoth K, Müller G, Raidt H (1976a) Isolierung und Charakterisierung zweier Hauptmetabolite von Ifosfamid aus Patientenurin. Arzneim Forsch 25:1376–1377
Norpoth K (1976b) Studies on the metabolism of isophosphamide (NSC-109724) in man. Cancer Treatm Rep 60:437–443
Peter G, Wagner T, Hohorst HJ (1976) Studies on 4-hydroperoxy-cyclophosphamide (NSC-181815): A simple preparation method and its application for the synthesis of a new class of “activated” sulfur-containing cyclophosphamide (NSC-26271) derivatives. Cancer Treatm Rep 60:429–435
Przybylski M, Ringsdorf H, Lenssen U, Peter G, Volecker G, Wagner T, Hohorst HJ (1977) Mass spectrometric characterization of activated N-(2-chloroethyl)amido oxazaphosphorine derivatives. Biomed Mass Spectrom 4:209–215
Sachs L (1969) Statistische Auswertungsmethoden, 2. Aufl. Springer, Berlin Heidelberg New York, S 293–300
Schaumlöffel E (1977) Vortrag, Internationales Holoxan-Symposion Düsseldorf (22.03.1977)
Sladek NE (1973) Bioassay and relative cytotoxic potency of cyclophosphamide metabolites generated in vitro and in vivo. Cancer Res 33:1150–1158
Struck RF, Kirk MC, Witt MH, Laster WR Jr (1975) Isolation and mass spectral identification of blood metabolites of cyclophosphamide: Evidence for phosphoramide mustard as the biologically active metabolite. Biomed Mass Spectrom 2:46–52
Voelcker G, Dräger U, Peter G, Hohorst HJ (1974) Studien zum Spontanzerfall von 4-Hydroxycyclophosphamid und 4-Hydroperoxycyclophosphamid mit Hilfe der Dünnschichtchromatographie. Arzneim Forsch 24:1172–1176
Voelcker G, Haeglsperger R, Hohorst HJ (1979) Fluorometrische Bestimmung von “aktiviertem” Cyclophosphamid und Ifosfamid im Blut. J Cancer Res Clin Oncol 93:233–240
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, Voelcker G, Hohorst HJ (1980) Über Blutspiegel und Urinausscheidung von aktiviertem Cyclophosphamid und seinen Deaktivierungsprodukten beim Menschen. J Cancer Res Clin Oncol 96:79–92
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Dedicated to Professor U. Ritter on his 60th birthday
With the support of the Bundesministerium für Forschung und Technologie, Bonn
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Wagner, T., Heydrich, D., Jork, T. et al. Comparative study on human pharmacokinetics of activated ifosfamide and cyclophosphamide by a modified fluorometric test. J Cancer Res Clin Oncol 100, 95–104 (1981). https://doi.org/10.1007/BF00405906
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DOI: https://doi.org/10.1007/BF00405906