Document Type

Article

Publication Date

7-15-2012

Publication Title

Journal of Chromatography B

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-d3-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.

Comments

This research was supported by the Cancer Pharmacology Core Facility of the Case Comprehensive Cancer Center (P30 CA43703) and the National Cancer Institute of the US National Institutes of Health (5R21CA126149).

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

DOI

10.1016/j.jchromb.2012.05.036

Version

Postprint

Volume

901

Download

Share

COinS