Urinary excretion of thioTEPA and its metabolites in patients treated with high-dose cyclophosphamide, thioTEPA and carboplatin

The urinary excretion of N,N′,N″-triethylenethiophosphoramide (thioTEPA), and its metabolites N,N′,N″-triethylene-phosphoramide (TEPA), N,N′-diethylene,N″-2-chloroethyl-phosphoramide (monochloroTEPA) and thioTEPA-mercapturate was determined in patients receiving thioTEPA as part of a high-dose combination chemotherapy regimen with cyclophosphamide and carboplatin. The thioTEPA dose was 40 or 60 mg/m² in short infusions, twice daily, during 4 days. Urine samples were collected after each voiding on each day of drug administration until 24-48 h after the last thioTEPA infusion. ThioTEPA, TEPA and monochloroTEPA concentrations were determined with gas chromatography and thioTEPA-mercapturate with liquid chromatography-mass spectrometry with direct sample injection. ThioTEPA was present in urine 30 min after infusion and was still excreted 18 h after the last infusion. All metabolites were detected in urine 1 h after infusion. Patients with a creatinine clearance above 140 ml/minl showed higher excretion of TEPA than patients with a creatinine clearance below 140 ml/min (12.8 versus 4.9%, p=0.01). The excretion of monochloro TEPA relative to the excreted amount of TEPA increased at lower pH values of the urine. The excretion of thioTEPA-mercapturate relative to the dose was higher in patients treated with 60 mg/m². Excretion of thioTEPA and monochloroTEPA both accounted for only 0.5% of the dose, while TEPA and thioTEPA-mercapturate both accounted for 11.1%.