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"-triethylenephosphoramide (TEPA), N,N'-diethylene,N"-2-chloroethylphosphoramide (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/m(2) 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 monochloroTEPA 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/m(2). Excretion of thioTEPA and monochloroTEPA both accounted for only 0.5% of the dose, while TEPA and thioTEPA--mercapturate both accounted for 11.1%.
van Maanen
M J
MJ
Division of Drug Toxicology, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands.
Huitema
A D
AD
Rodenhuis
S
S
Beijnen
J H
JH
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000652:urine*; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001388:Aziridines / Q000652:urine*; D001943:Breast Neoplasms / Q000652:urine; D016190:Carboplatin / Q000008:administration & dosage*; D003404:Creatinine / Q000652:urine; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009373:Neoplasms, Germ Cell and Embryonal / Q000652:urine; D013852:Thiotepa / Q000008:administration & dosage* / Q000378:metabolism* / Q000652:urine*; D013997:Time Factors; D013721:Triethylenephosphoramide / Q000652:urine
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D001388:Aziridines; C411825:N,N'-diethylene-N''-2-chloroethylphosphoramide; C411826:thioTEPA-mercapturate; D003520:Cyclophosphamide; D013852:Thiotepa; D003404:Creatinine; D016190:Carboplatin; D013721:Triethylenephosphoramide; D000111:Acetylcysteine