Determination of atomoxetine metabolites in human plasma by liquid chromatography/tandem mass spectrometry and its application to a pharmacokinetic study
- Authors
- Choi, Chang-Ik; Bae, Jung-Woo; Lee, Hye-In; Jang, Choon-Gon; Sohn, Uy Dong; Lee, Seok-Yong
- Issue Date
- Feb-2012
- Publisher
- ELSEVIER SCIENCE BV
- Keywords
- 4-Hydroxyatomoxetine; N-Desmethylatomoxetine; LC-MS/MS; Human plasma; Pharmacokinetics
- Citation
- JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, v.885, pp 103 - 108
- Pages
- 6
- Journal Title
- JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
- Volume
- 885
- Start Page
- 103
- End Page
- 108
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/20511
- DOI
- 10.1016/j.jchromb.2011.12.023
- ISSN
- 1570-0232
1873-376X
- Abstract
- 4-Hydroxyatomoxetine (4-HAT) and N-desmethylatomoxetine (N-DAT) are major metabolites of atomoxetine, a potent and selective inhibitor of the presynaptic norepinephrine transporter that is used for the treatment of attention deficit/hyperactivity disorder. The pharmacological activity of 4-HAT is similar to that of atomoxetine. We have developed and validated a simple, rapid and sensitive liquid chromatography analytical method with tandem mass spectrometry (LC-MS/MS) for the determination of 4-HAT and N-DAT in human plasma. After liquid-liquid extraction with methyl t-butyl ether, chromatographic separation of analytes was performed using a reversed-phase Luna C-18 column (2.0 mm x 100 mm, 3 vim particles) with a mobile phase of 10 mM ammonium formate buffer (pH 3.5)-methanol (10:90, v/v) and quantified by MS/MS detection in ESI positive ion mode. The flow rate of the mobile phase was 250 mu L/min and the retention times of 4-HAT, N-DAT and internal standard (IS, metoprolol) were 0.9, 1.0 and 1.0 min, respectively. The calibration curves were linear over the range of 0.05-20 ng/mL for 4-HAT and 0.1-20 ng/mL for N-DAT. The lower limits of quantification, using 200 mu L human plasma, were 0.05 and 0.1 ng/mL for 4-HAT and N-DAT, respectively. The mean accuracy and precision for intra- and inter-day validation of 4-HAT and N-DAT were both within the acceptable limits. This LC-MS/MS method showed improved sensitivity for quantification of the two main metabolites of atomoxetine in human plasma compared with previously described analytical methods. The validated method was successfully applied to a pharmacokinetic study in humans. (C) 2011 Elsevier B.V. All rights reserved.
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