Repeated high-dose cyclophosphamide administration in bone marrow transplantation: exposure to activated metabolites

Summary

Blood levels of cyclophosphamide (CP) and activated metabolites were measured in 11 patients undergoing a 2- to 4-day conditioning chemotherapy for bone marrow transplantation. Urinary excretion of CP was determined in five patients. CP half-life decreased after pretreatment from an average of 7.1 h on the 1st day to 5.5 h on the 2nd day (P<0.005) and to 4.3 h on the 4th day (P<0.005). No characteristic changes in urinary excretion could be observed. At the same time the exposure to nonprotein-bound activated metabolites increased from 10.5 to 19.5 and 26.0 nmolxh/ml respectively (P<0.005 andP<0.04). Thus, in contrast to in vitro and animal studies, no evidence for an inhibition of activating enzymes could be found. On the contrary, pretreatment seems to enhance the production of the cytotoxic metabolites. The possible explanation of these changes by enzyme induction and by the role of saturated protein binding sites is discussed. Exposure to active metabolites might be altered by dose splitting or even by a change in the duration of the infusion.