title: Development and validation of an LC-MS/MS method for pharmacokinetic study of methoxyamine in phase I clinical trial.
abstract: Methoxyamine (MX) is the first DNA base-excision-repair (BER) inhibitor evaluated in humans. This work described the development and validation of an LC-MS/MS method for quantitative determination of MX in human plasma. In this method, MX and its stable isotope methoxyl-d(3)-amine (MX-d3 as internal standard) were directly derivatized in human plasma with 4-(N,N-diethylamino)benzaldehyde. The derivatized MX and IS were extracted by methyl-tert-butyl ether, and separated isocratically on a Xterra C18 column (2.1 mm × 100 mm) using an aqueous mobile phase containing 45% acetonitrile and 0.4% formic acid at a flow rate of 0.200 ml/min. Quantitation of MX was carried out by multiple-reaction-monitoring (MRM) mode of positive turbo-ion-spray tandem mass spectrometry. This method has been validated according to FDA guidelines for bioanalytical method. The linear calibration range for MX was 1.25-500 ng/ml in human plasma with a correlation coefficient≥0.9993. The intra- and inter-assay precision (%CV) at three concentration levels (3.50, 45.0 and 450 ng/ml) ranged 0.9-1% and 0.8-3%, respectively. The stability studies showed that MX met the acceptable criteria under all tested conditions. The method developed had been applied to the determination of plasma MX concentrations in the first-in-human phase I clinical trial, and PK data were presented.
authors: Case Comprehensive Cancer Center, Case Western Reserve University, and Seidman Cancer Center, University Hospitals, Case Medical Center, Cleveland, OH 44106, USA.
authors: Shuming
authors: S
authors: Yang
authors: Panayiotis
authors: P
authors: Savvides
authors: Lili
authors: L
authors: Liu
authors: Stanton L
authors: SL
authors: Gerson
authors: Yan
authors: Y
authors: Xu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001547:Benzaldehydes / Q000737:chemistry; D002853:Chromatography, Liquid / Q000379:methods*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004355:Drug Stability; D006801:Humans; D006898:Hydroxylamines / Q000008:administration & dosage / Q000097:blood / Q000302:isolation & purification / Q000493:pharmacokinetics*; D016014:Linear Models; D059625:Liquid-Liquid Extraction; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*; D000077204:Temozolomide
chemical_list: D001547:Benzaldehydes; D006898:Hydroxylamines; C055506:4-(diethylamino)benzaldehyde; D003606:Dacarbazine; C005214:methoxyamine; D000077204:Temozolomide