Blood levels and alkylating metabolites of cyclophosphamide in the mouse after Iv or oral administration

Blood levels of cyclophosphamide (CPA) and its alkylating metabolites in mice were determined after iv or oral administration of a 200-mg/kg dose of radiolabeled CPA. Individual metabolites (4-hydroxy-CPA, 4-keto-CPA, alcophosphamide, dechloroethyl-CPA, carboxyphosphamide, and phosphoramide mustard) were isolated from blood by solvent extraction and by thin-layer chromatography. Area-under-the-blood-decay-curve (AUC) values were determined for CPA and its alkylating metabolites to provide a basis for comparison of systemic exposure by iv or oral treatment. The total AUC values for alkylating metabolites of CPA was observed to be greater after iv administration, and AUC values for each of the individual metabolites were greater after iv treatment, except for the minor metabolite alcophosphamide. The methods in this study have been applied to one patient to data and will be used in future studies with other patients to determine relative AUC values for the oncolytic CPA metabolites 4-hydroxy-CPA and phosphoramide mustard.