Monitoring of N,N-dimethylacetamide in children during i.v.-busulfan therapy by liquid chromatography-mass spectrometry.
Recently, an intravenous (i.v.) formulation of busulfan using the potentially hepatotoxic and neurotoxic N,N-dimethylacetamide (DMA) as a solvent was introduced. There is a need to assess the exposure of DMA in patients during the intravenous high dose therapy. A rapid and selective LC-MS method was developed to quantify relevant DMA concentration in plasma. After protein precipitation with trichloroacetic acid, the isocratic separation was achieved using a 150 mm x 2 mm C18 column and elution with a mobile phase containing 0.1% formic acid in water/acetonitrile (97:3). Detection of DMA was carried out with a ThermoFinnigan single-quadrupole mass spectrometer in selected-ion monitoring mode as H+ -adduct at m/z 88.2. Deuterium-labelled DMA was used as the internal standard. The LC-MS method was accurate, precise and reproducible in the range from 0.25 to 150 mg/l and met the generally accepted criteria for bioanalytical methods. Two calibration ranges from 0.25 to 7.5 mg/l and 7.5 to 150 mg/l were used. The intra- (n = 7) and interassay (n = 7) accuracy and precision were both < 7.7% and the limit of quantification is 0.25 mg/l. The method was successfully applied to investigate 203 plasma samples in children during the i.v.-busulfan therapy.
Oechtering
Doris
D
Klinik und Poliklinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie/Onkologie, Albert-Schweitzer-Str. 33, 48129 Muenster, Germany.
Boos
Joachim
J
Hempel
Georg
G
D000081:Acetamides / Q000097:blood* / Q000737:chemistry / Q000592:standards; D000293:Adolescent; D002066:Busulfan / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid / Q000379:methods*; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D013058:Mass Spectrometry / Q000379:methods*; D012015:Reference Standards; D015203:Reproducibility of Results; D012997:Solvents / Q000737:chemistry
D000081:Acetamides; D012997:Solvents; D002066:Busulfan; C013959:dimethylacetamide