Quantification of dimethyl-ifosfamide and its N-deschloropropylated metabolites in mouse plasma by liquid chromatography-tandem mass spectrometry.
J Chromatogr B Analyt Technol Biomed Life Sci
; 879(11-12): 743-50, 2011 Apr 01.
Article
en En
| MEDLINE
| ID: mdl-21377940
ABSTRACT
Among antitumor oxazaphosphorine drugs, the prodrug ifosfamide (IFO) and its analogs require metabolic activation by specific liver cytochrome P450 (CYP) enzymes to become therapeutically active. New 7,9-dimethyl-ifosfamide analogs have shown greater cytotoxic activity than IFO, whereas side-chain oxidation still occurred leading to monochloroacetone after N-dechloropropylation. A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated for the simultaneous quantitation of the prodrug 7S,9S-dimethyl-ifosfamide (diMeIFO) and its two inactive metabolites, N(2)- and N(3)-deschloropropyl-dimethylifosfamide (N(2)-DCP-diMeIFO and N(3)-DCP-diMeIFO) in mouse plasma. After protein precipitation with methanol, the analytes were separated by isocratic reversed-phase chromatography with (methanol/ammonium formate pH 5.5, 6040, v/v) and detected by tandem mass spectrometry using multiple reaction monitoring of transitions ions m/z 289â168 for diMeIFO, m/z 213â168 for N(2)-DCP-diMeIFO, m/z 213â92 for N(3)-DCP-diMeIFO and m/z 261â154 for IFO (internal standard). The calibration curves were linear over the concentration range of 20-10,000ng/mL for the three analytes. Mean extraction recoveries from mouse plasma were 99, 96, 99 and 100% for diMeIFO, N(2)-DCP-diMeIFO, N(3)-DCP-diMeIFO and IFO, respectively. The lower limit of quantitation for diMeIFO and its metabolites was 20 ng/mL in 50 µL plasma. The method was accurate with calculated bias from -5.8 to 4.0% for diMeIFO, from -1.1 to 10.6% for N(2)-DCP-diMeIFO and from -6.9 to 9.8% for N(3)-DCP-diMeIFO, and precise with coefficients of variation lower than 6.8%, 7.8% and 14.3%, respectively. The assay was successfully applied to a preliminary pharmacokinetic study of diMeIFO and of its metabolites in mice.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Cromatografía Liquida
/
Espectrometría de Masas en Tándem
/
Ifosfamida
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Chromatogr B Analyt Technol Biomed Life Sci
Asunto de la revista:
ENGENHARIA BIOMEDICA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Francia