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- Title
Investigations on the pharmacokinetics of trofosfamide and its metabolites—first report of 4-hydroxy-trofosfamide kinetics in humans.
- Authors
Preiss, Rainer; Baumann, Frank; Stefanovic, Dragan; Niemeyer, Ulf; Pünisch, Wolfgang; Niederwieser, Dietger
- Abstract
Trofosfamide (TRO), like cyclophosphamide (CYCLO) and ifosfamide (IFO), is a prodrug oxazaphosphorine derivative that requires hepatic biotransformation to form the cytotoxically active 4-hydroxy derivative (4-hydroxy-TRO). Individual 4-hydroxyoxazaphosphorines and 4-hydroxy-TRO itself have not been demonstrated in humans up to now. For investigation of the principal pharmacokinetics of TRO and its metabolites, six tumour patients (49–65 years of age, Karnofsky index >70%) with normal liver and renal function were given a single oral dose of 600 mg/m2 TRO. Plasma was sampled using a bedside technique. Individual 4-hydroxyoxazaphosphorines and TRO together with further metabolites were determined by a specially developed HPLC-UV method and a HPLC-MS method, respectively. With a short apparent half-life (1.2 h) and high apparent clearance (Cl/F 4.0 l/min), TRO was very quickly eliminated from plasma and highly converted to its metabolites, mainly 4-hydroxy-TRO and IFO. In relation to the AUC values of TRO (1.0) the following molar quotients were calculated: 1.59 (4-hydroxy-TRO), 0.40 (4-hydroxy-IFO), 6.90 (IFO) and 0.74 (CYCLO). Cmax values were in the range 10–13 μmol/l for TRO, 4-hydroxy-TRO and IFO and in the range 1.5–4.0 μmol/l for CYCLO, 2- and 3-dechloroethyl-IFO and 4-hydroxy-IFO. Kinetic data indicate that 4-hydroxy-IFO is formed by both hydroxylation of TRO and exocyclic N-dechloroethylation of 4-hydroxy-TRO. 4-hydroxy-CYCLO was not detected above the quantification limit of the method. Only mild haemodepressive side effects were observed after oral administration of 600 mg/m2 TRO. In relation to known data for IFO, TRO is much more 4-hydroxylated than IFO. The high 4-hydroxy-TRO/TRO ratio found suggests that TRO is a promising tumourstatic agent.
- Subjects
METABOLITES; BIOMOLECULES; TUMORS; DRUG metabolism; CHEMICAL kinetics; BILIARY tract
- Publication
Cancer Chemotherapy & Pharmacology, 2004, Vol 53, Issue 6, p496
- ISSN
0344-5704
- Publication type
Article
- DOI
10.1007/s00280-003-0757-y