Summary
Blood levels and urinary excretion of cyclophosphamide and its metabolites were determined in cancer patients receiving cyclophosphamide. Activated cyclophosphamide (4-hydroxycyclophosphamide+aldophosphamide) was assayed by TLC after derivatisation to stable 4-(S-benzyl)-sulfido-cyclophosphamide. Twenty minutes after injection of 10(20) mg/kg cyclophosphamide mean peak levels of activated cyclophosphamide were found to be 1.4 (2.6) nmol/ml. The rate constant for biotransformation (=activation) of cyclophosphamide in man (k m=0.132 h-1) was only 1/50 of the value found in the mouse whereas the elimination rate constant of activated cyclophosphamide (k e[M]∼6.78 h-1) was much higher equalling that of laboratory animals.
4-ketocyclophosphamide, carboxyphosphamide, and phosphoramidemustard reached their peak levels between 4 and 6 h after cyclophosphamide injection. Increasing quantities of cyclophosphamide metabolites were bound to plasma proteins reaching a constant level after 24 h lasted for several days. Fifty per cent of those metabolites were reversibly bound to plasma proteins. Within 24 h, the cumulative excretion of cyclophosphamide and its metabolites amounted to 50% of the dose applied. The main metabolites excreted were phosphoramide-mustard and carboxyphosphamide whereas only 2% consited of activated cyclophosphamide. The significance of the different pharmacokinetics of cyclophosphamide in laboratory animals and man for the therapeutic index is discussed.
Zusammenfassung
Bei krebskranken Patienten wurden während der Chemotherapie mit Cyclophosphamid Blutspiegel und Urin-Ausscheidung von Cyclophosphamid und seinen Metaboliten bestimmt. Aktiviertes Cyclophosphamid (4-Hydroxycyclophosphamid+Aldophosphamid) wurde nach Derivatisierung zum stabilen 4-(S-Benzyl)-sulfido-Cyclophosphamid nachgewiesen. 20 min nach Injektion von 10(20) mg/kg Cyclophosphamid wurden im Mittel 1,4(2,6) nmol/ml aktiviertes Cyclophosphamid gefunden. Die Aktivierungsrate von Cyclophosphamid wies beim Menschen mit einer Konstante von k m=0,132 h-1 nur 1/50 des bei der Maus gefundenen Wertes auf, während die Eliminationskonstante des aktivierten Cyclophosphamid (k e[M]∼6,78 h-1) weitaus größer war und die gleiche Größenordnung wie beim Laboratoriumstier zeigte. 4-Ketocyclophosphamid, Carboxyphosphamid und N-Lost-Phosphorsäurediamid erreichten zwischen 4 und 6 h nach Cyclophosphamid-Injektion ihre Maximalspiegel im Blut. Wachsende Antiele der metabolite werden an Plasma-Proteine gebunden und nach 24 h ein über Tage andauernder konstanter Spiegel von Protein-gebundenen Cyclophosphamid-Metaboliten erreicht, von dem die Hälfte aus reversibel gebundenen Metaboliten besteht. Die kumulative Ausscheidung von Cyclophosphamid und seinen Metaboliten betrug 50% der applizierten Dosis innerhalb 24 h. Hauptausscheidungsprodukte waren N-Lost-Phosphorsäurediamid und Carboxyphosphamid, wohingengen der Anteil aktivierten Cyclophosphamids an den Urinmetaboliten nur 2% betrug.
Die Bedeutung der bei Tier und Mensch unterschiedlichen Pharmakokinetik von Cyclophosphamid für seine therapeutische Breite wird diskutiert.
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Wagner, T., Heydrich, D., Voelcker, G. et al. Über Blutspiegel und Urin-Ausscheidung von aktiviertem Cyclophosphamid und seinen Deaktivierungsprodukten beim Menschen. J Cancer Res Clin Oncol 96, 79–92 (1980). https://doi.org/10.1007/BF00412899
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DOI: https://doi.org/10.1007/BF00412899