Synthesis of the major metabolites of Paroxetine

Segura, Mireia; Roura, Lidia; Torre, Rafael de la; Joglar, Jesús

doi:10.1016/s0045-2068(03)00040-3

Cited by 13 publications

(9 citation statements)

References 10 publications

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“…In humans, 127 undergoes metabolism by COMT to afford isomeric guaiacol metabolites 128 and 129 that are excreted as the corresponding glucuronide and sulfate conjugates (see Fig. 34) [230,231].…”

Section: Occurrence and Frequencymentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

584

507

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The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.

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Section: Occurrence and Frequencymentioning

confidence: 99%

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Kalgutkar¹,

Gardner²,

Obach³

et al. 2005

CDM

584

507

View full text Add to dashboard Cite

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“…Paroxetine and its metabolites were also identified in an extracted saliva sample. Segura et al 46. have described the synthesis of the major metabolites of paroxetine and have determined paroxetine and its metabolite in plasma using HPLC/MS 47…”

Section: Resultsmentioning

confidence: 99%

An electrospray ionisation tandem mass spectrometric investigation of selected psychoactive pharmaceuticals and its application in drug and metabolite profiling by liquid chromatography/electrospray ionisation tandem mass spectrometry

Doherty

González-Rodríguez

Leslie

et al. 2007

Rapid Comm Mass Spectrometry

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A tandem mass spectrometric investigation of the collision-induced dissociation of five commonly prescribed psychoactive pharmaceuticals, risperidone, sertraline, paroxetine, trimipramine, and mirtazapine, and their metabolites has been carried out. Quadrupole ion trap mass spectrometry was employed to generate tandem mass spectrometric (MS/MS) data of the compounds under investigation and structural assignments of product ions were supported by quadrupole time-of-flight mass spectrometry. These fragmentation studies were then utilised in the development of a liquid chromatographic method to identify the drugs and their metabolites in human hair and saliva samples, thus providing relevant profiling information.

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“…Paroxetine, (3 S ,4 R )‐(4‐(4‐fluorophenyl)‐3‐(3,4‐methylenedioxyphenoxymethyl)piperidine), and HM paroxetine, ((3 S ,4 R )‐4‐(4‐fluorophenyl)‐3‐(4‐hydroxy‐3‐methoxyphenoxymethyl)piperidine), were synthesised in the “Centro de Investigación y Desarrollo of Centro Superior de Investigaciones Científicas” (CID‐CSIC, Barcelona, Spain). Details of the preparation of standards are described elsewhere 11. Pholedrine (4‐hydroxy‐ N , α ‐dimethylphenethylamine) was kindly donated by the Biochemistry Department of the Deutsche Sporthochschule (Cologne, Germany).…”

Section: Methodsmentioning

confidence: 99%

Quantitative determination of paroxetine and its 4‐hydroxy‐3‐methoxy metabolite in plasma by high‐performance liquid chromatography/electrospray ion trap mass spectrometry: application to pharmacokinetic studies

Segura

Ortuño

Farré

et al. 2003

Rapid Comm Mass Spectrometry

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A high-performance liquid chromatography (HPLC) method with tandem mass spectrometric detection is described for the determination of paroxetine, an antidepressant drug, and its metabolite (3S,4R)-4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl)piperidine (HM paroxetine) in human plasma. Plasma samples were hydrolysed with hydrochloric acid and then analytes were extracted with ethyl acetate at alkaline pH. Extracts were analysed by HPLC coupled to an atmospheric pressure ionisation-electrospray (ESI) interface and an ion trap mass spectrometer. Chromatography was performed on a reversed-phase column using acetonitrile/0.02% formic acid (66:34, v/v) as a mobile phase. The mass spectrometer was operated in the multiple reaction monitoring mode. The method was validated over concentration ranges of 0.75-100 microg/L and 5-100 microg/L for paroxetine and HM paroxetine, respectively. Mean recoveries of 77% for paroxetine and 76% for HM paroxetine were found, with precision always better than 15%. The limits of detection and quantification were 0.20 and 0.70 microg/L for paroxetine, and 0.70 and 2.20 microg/L for its metabolite. The method was applied to the analysis of plasma samples obtained from nine healthy male volunteers administered with a single oral dose of 20 mg paroxetine. After the 20-mg dose, the mean peak plasma concentration was 8.60 microg/L for paroxetine and 92.40 microg/L for HM paroxetine showing a tenfold ratio between the metabolite and the parent drug along the entire time-concentration curve.

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Synthesis of the major metabolites of Paroxetine

Cited by 13 publications

References 10 publications

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

An electrospray ionisation tandem mass spectrometric investigation of selected psychoactive pharmaceuticals and its application in drug and metabolite profiling by liquid chromatography/electrospray ionisation tandem mass spectrometry

Quantitative determination of paroxetine and its 4‐hydroxy‐3‐methoxy metabolite in plasma by high‐performance liquid chromatography/electrospray ion trap mass spectrometry: application to pharmacokinetic studies

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