Metabolic pathway of paroxetine in animals and man and the comparative pharmacological properties of its metabolites

Haddock, R. E.; Johnson, Ann; Langley, P. F.; Nelson, David R.; Pope, Jamie; Thomas, D R; Woods, F. R.

doi:10.1111/j.1600-0447.1989.tb07163.x

Cited by 87 publications

(60 citation statements)

References 2 publications

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“…The carbene intermediate can complex to the heme iron in P450 to yield the characteristic type 3 spectrum (Ortiz de Montellano and Correia, 1995). Paroxetine possesses a methylenedioxyphenyl substituent and is metabolized to a catechol metabolite (Haddock et al, 1989). This finding supports the mechanism of paroxetine inactivation of CYP2D6 as occurring via formation of a carbene-heme MIC.…”

Section: Paroxetine Inhibition Of Cyp2d6supporting

confidence: 71%

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Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

Bertelsen

Venkatakrishnan²,

Moltke³

et al. 2003

Drug Metab Dispos

250

174

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of cytochrome P450 2D6 (CYP2D6) activity, but the mechanism of inhibition is not established. To determine whether preincubation affects the inhibition of human liver microsomal dextromethorphan demethylation activity by paroxetine, we used a twostep incubation scheme in which all of the enzyme assay components, minus substrate, are preincubated with paroxetine. The kinetic parameters of inhibition were also estimated by varying the time of preincubation as well as the concentration of inhibitor.

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Section: Paroxetine Inhibition Of Cyp2d6supporting

confidence: 71%

“…Paroxetine is metabolized by CYP2D6 via demethylenation of the methylenedioxy group, yielding a catechol metabolite and formic acid (Haddock et al, 1989;Bloomer et al, 1992). Paroxetine inhibits CYP2D6 activity at IC 50 concentrations ranging from 150 nM to 2.0 M, depending on the substrate (Crewe et al, 1992;von Moltke et al, 1995;Fogelman et al, 1999).…”

mentioning

confidence: 99%

Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

Bertelsen

Venkatakrishnan²,

Moltke³

et al. 2003

Drug Metab Dispos

250

174

View full text Add to dashboard Cite

show abstract

“…In such a situation, quite different from that present in chronic studies, compensatory increases in 5-HT metabolism might have occurred in an attempt to overcome the initial autoreceptor-mediated reduction in 5-HT release and synthesis. However, given the relatively long half-life (20 h) of PAR (Haddock et al, 1989), it is unlikely that substantial decreases in reuptake inhibition occurred before the 1 pm or 4 pm CSF samples were obtained. We did not measure CSF or plasma PAR concentrations, or other peripheral indices of 5-HT function that would have provided additional information about the possible contribution of relevant pharmacokinetic variables.…”

Section: Discussionmentioning

confidence: 99%

“…PAR has no major metabolite and its absorption is not altered by a fast or fed state (Haddock et al, 1989). In addition, PAR is in wide clinical use, is welltolerated at a dose of 40 mg/day, and has been reported to be an effective serotonergic neuroendocrine probe, with a single 40 mg oral dose provoking a significant increase in serum cortisol 3 h after ingestion (Reist et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Acute changes in Cerebrospinal Fluid 5-HIAA following Oral Paroxetine Challenge in Healthy Humans

Carpenter

Anderson

Siniscalchi

et al. 2003

Neuropsychopharmacol

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A number of studies have reported decreased human lumbar cerebrospinal fluid (CSF) concentrations of the major serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), following chronic administration of selective serotonin reuptake inhibitors (SSRIs). This decrease has been thought to be a consequence of elevated extracellular serotonin and to be mediated through terminal autoreceptor feedback inhibition of serotonin turnover. We wished to study the previously unexamined acute effects of SSRI administration on human CSF 5-HIAA. A serial lumbar puncture (LP) procedure was used to collect CSF samples before and after a single oral 40 mg dose of the SSRI paroxetine (PAR) or matching placebo in eight healthy adult humans in a randomized, double-blind fashion. CSF 5-HIAA concentrations did not change following placebo, but showed a statistically significant 27% mean increase 3 h following PAR. Our findings stand in contrast to the decreases reported for CSF 5-HIAA after chronic SSRI treatment in humans and the decreases seen in brain extracellular 5-HIAA after acute or chronic administration of SSRIs to animals.

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“…For incubation with SCH, day 4 hepatocytes were incubated statically with 0.5 ml of 1 mM [ 3 H]paroxetine in WME in the incubator (37°C, 5% carbon dioxide) for 0, 0.25, 0.5, 1, 3, 6, and 24 hours. Each incubation was terminated by adding 0.5 ml of Haddock et al (1989), Kaye et al (1989), andJornil et al (2010).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Hepatic Disposition of Paroxetine Using Sandwich-Cultured Rat and Human Hepatocytes

et al. 2013

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Paroxetine, a selective serotonin reuptake inhibitor, is metabolized in the liver and excreted into bile and urine as metabolites, but species differences have been observed in hepatic disposition between rats and humans. A major metabolite in rats is M1-glucuronide, whereas M1-glucuronide and M1-sulfate are found in humans. The primary excretion route of paroxetine-derived radioactivity in rats and humans is bile and urine, respectively. The aim of this study was to examine the usefulness of sandwich-cultured hepatocytes (SCH) to evaluate in vivo species differences of the hepatic disposition of paroxetine between rats and humans. The metabolite profile of [ 3 H]paroxetine in SCH was similar to that in hepatocytes in suspension, and the in vitro metabolite profiles were similar to the published in vivo metabolic pathways for both species. Furthermore, the biliary excretion index (BEI) of formed M1-glucuronide in rat SCH (25.8-50.9%) was higher than that in human SCH (15.1-16.7%). The BEI of formed M1-sulfate (16.4-29.1%) was comparable to that of M1-glucuronide in human SCH, whereas the BEIs of paroxetine were negligible in SCH of both species. Moreover, M1-glucuronide was demonstrated to be a multidrug resistance-associated protein 2 substrate in both species, as determined by its uptake into ATP-binding cassette transporter-expressing membrane vesicles. SCH should prove to be useful to evaluate the processes of hepatic uptake and metabolism of parent drugs and the simultaneous examination of the biliary excretion of both parent drug and liver-derived metabolites.

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Metabolic pathway of paroxetine in animals and man and the comparative pharmacological properties of its metabolites

Cited by 87 publications

References 2 publications

Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

Acute changes in Cerebrospinal Fluid 5-HIAA following Oral Paroxetine Challenge in Healthy Humans

Evaluation of Hepatic Disposition of Paroxetine Using Sandwich-Cultured Rat and Human Hepatocytes

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