Determination of 4-hydroxyifosfamide concomitantly with ifosfamide and its dechloroethylated metabolites using gas chromatography and a nitrogen phosphorus-selective detector.
A sensitive gas chromatographic (GC)/nitrogen phosphorus detection (NPD) system was developed for the determination of the antitumor drug ifosfamide (Ifos) and its 2-dechloroethylifosfamide (2-Difos), 3-dechloroethylifosfamide (3-Difos) and 4-hydroxyifosfamide (4-OHIfos) metabolites in human blood. 4-OHIfos was analyzed after coupling with a trapping agent and was used as an indicator of isophosphoramide mustard (IPM). Ifos and its metabolites 2-DIfos, 3-DIfos, 4-OHIfos and the internal standard (trofosfamide) were extracted into chloroform and then resolved by gas chromatography using a Hewlett Packard HP5 capillary column cross-linked with 5% phenyl methyl silicone (30 m; 530 microm I.D.; 2.65 microm film thickness). Precision and accuracy of the assay were determined over a three-day period and a concentration range of 3.25-50 microg/ml for Ifos, 0.8-14 microg/ml for 2D-Ifos, 0.6-10 microg/ml for 3D-Ifos and 0.08-1.40 microg/ml for 4-OHIfos. The limit of quantitation was set at 3.25, 0.80, 0.62 and 0.08 microg/ml, respectively, for Ifos, 2-DIfos, 3-DIfos and 4-OHIfos. The intra- and inter-day coefficients of variation and accuracies were less than 20%, except for a low concentration 4-OHIfos. This assay was then used to provide pharmacokinetic data on antitumor and toxicologic effects following intravenous infusion of Ifos.
Gourmel
B
B
Laboratoire de Biochimie, Hôpital Saint-Louis, Paris, France.
Granvil
C P
CP
Denis
S L
SL
Wainer
I W
IW
Bousquet
B
B
D018906:Antineoplastic Agents, Alkylating / Q000032:analysis / Q000493:pharmacokinetics; D002849:Chromatography, Gas / Q000379:methods*; D006801:Humans; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000032:analysis* / Q000493:pharmacokinetics; D013058:Mass Spectrometry; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D018906:Antineoplastic Agents, Alkylating; C039771:4-hydroxyifosfamide; D007069:Ifosfamide