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 (2.0mm×100mm, 3μm particles) with a mobile phase of 10mM 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 250μL/min and the retention times of 4-HAT, N-DAT and internal standard (IS, metoprolol) were 0.9, 1.0 and 1.0min, respectively. The calibration curves were linear over the range of 0.05-20ng/mL for 4-HAT and 0.1-20ng/mL for N-DAT. The lower limits of quantification, using 200μL human plasma, were 0.05 and 0.1ng/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.
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Authors | Chang-Ik Choi, Jung-Woo Bae, Hye-In Lee, Choon-Gon Jang, Uy Dong Sohn, Seok-Yong Lee |
Journal | Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
(J Chromatogr B Analyt Technol Biomed Life Sci)
Vol. 885-886
Pg. 103-8
(Feb 15 2012)
ISSN: 1873-376X [Electronic] Netherlands |
PMID | 22237133
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 Elsevier B.V. All rights reserved. |
Chemical References |
- Phenols
- Phenyl Ethers
- Propylamines
- N-desmethylatomoxetine
- Atomoxetine Hydrochloride
- 4-hydroxyatomoxetine
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Topics |
- Atomoxetine Hydrochloride
- Chromatography, Liquid
(methods)
- Drug Stability
- Humans
- Male
- Phenols
(blood, pharmacokinetics)
- Phenyl Ethers
(blood, pharmacokinetics)
- Propylamines
(blood, metabolism, pharmacokinetics)
- Reproducibility of Results
- Sensitivity and Specificity
- Tandem Mass Spectrometry
(methods)
- Young Adult
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