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Paroxetine

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Paroxetine Basic information
Paroxetine Chemical Properties
Safety Information
  • RIDADR 3249
  • HazardClass 6.1(b)
  • PackingGroup III
Paroxetine Usage And Synthesis
  • DescriptionParoxetine is a new highly selective serotonin reuptake inhibitor, mechanistically similar to fluoxetine, fluvoxamine and sertraline, introduced for the treatment of all types of depressive illnesses including depression associated with anxiety. It is reportedly non-sedating and non-stimulatory and compared to fluoxetine has a shorter duration of action (half-life of 24 hours versus 2 to 3 days). Paroxetine is also being investigated as a treatment for obesity, alcoholism and obsessive-compulsive disorders.
  • Chemical PropertiesWhite Solid
  • OriginatorAs Ferrosan (Novo-Nordisk) (Denmark)
  • UsesA istopically labelled selective serotonin reuptake inhibitor. Used as an antidepressant
  • brand namePaxil[as hydrochloride] (SmithKline Beecham);Seroxat.
  • Biological FunctionsParoxetine (Paxil) has an elimination half-life of 21 hours and is also highly bound to plasma proteins, so it requires special attention when administered with drugs such as warfarin. Paroxetine is a potent inhibitor of the cytochrome P450 2D6 isoenzyme and can raise the plasma levels of drugs metabolized via this route. Of particular concern are drugs with a narrow therapeutic index, such as TCAs and the type 1C antiarrhythmics flecainide, propafenone, and encainide. Additionally, paroxetine itself is metabolized by this enzyme and inhibits its own metabolism, leading to nonlinear kinetics. Weight gain is higher with paroxetine than with the other SSRIs, and it tends to be more sedating, presumably because of its potential anticholinergic effects. Additionally, patients have had difficulty with abrupt discontinuation with this agent, reporting a flulike syndrome; this symptom can be avoided by tapering the medication.
  • General DescriptionIn the structure of paroxetine (Paxil), an amino group, protonatedin vivo could H-bond with the–CH2–O– unshared electrons.A β-arylamine–like structure with an extra aryl groupresults. The compound is a very highly selective SERT. Asexpected, it is an effective antidepressant and anxiolytic.
  • PharmacokineticsParoxetine appears to be slowly but well absorbed from the GItract following oral administration with an oral bioavailability of approximately 50%, suggesting first-pass metabolism, reaching peak plasma concentrations in 2 to 8 hours. Food does not substantially affect the absorption of paroxetine. Paroxetine is distributed into breast milk. Approximately 80% of an oral dose of paroxetine is oxidized by CYP2D6 to a catechol intermediate, which is then either O-methylated or O-glucuronidated. These conjugates are then eliminated in the urine.
    Paroxetine exhibits a preincubation-dependent increase in inhibitory potency of CYP2D6 consistent with a mechanism-based inhibition of CYP2D6. The inactivation of CYP2D6 occurs via the formation of an o-quinonoid reactive metabolite.
    The methylenedioxy has been associated with mechanism-based inactivation of other CYP isoforms. In contrast, fluoxetine, a potent inhibitor of CYP2D6 activity, did not exhibit a mechanism-based inhibition of CYP2D6. As a result of mechanism-based inhibition, saturation of CYP2D6 at clinical doses appears to account for its nonlinear pharmacokinetics observed with increasing dose and duration of paroxetine treatment, which results in increased plasma concentrations of paroxetine at low doses. The elderly may be more susceptible to changes in doses and, therefore, should be started off at lower doses. Following oral administration, paroxetine and its metabolites are excreted in both urine and feces.
    Oral administration of a single dose resulted in unmetabolized paroxetine accounting for 2% and metabolites accounting for 62% of the excretion products. The effect of age on the elimination of paroxetine suggests that hepatic clearance of paroxetine can be reduced, leading to an increase in elimination half-life (e.g., to ~36 hours) and increased plasma concentrations. The metabolites of paroxetine have been shown to possess no more than 2% of the potency of the parent compound as inhibitors of 5-HT reuptake; therefore, they are essentially inactive.
    Because paroxetine is a potent mechanism-based inhibitor of CYP2D6, this type of inhibition yields nonlinear and long-term effects on drug pharmacokinetics, because the inactivated or complexed CYP2D6 must be replaced by newly synthesized CYP2D6 protein. Thus, coadministration of paroxetine with CYP2D6- metabolized medications should be closely monitored or, in certain cases, avoided, as should upward dose adjustment of paroxetine itself.
  • Clinical Use In vitro binding studies suggest that paroxetine is a more selective and potent inhibitor of 5-HT reuptake than fluoxetine. The drug essentially has no effect on NE or dopamine reuptake, nor does it show affinity for other neuroreceptors. Its onset of action is 1 to 4 weeks.
  • Veterinary Drugs and TreatmentsParoxetine may be beneficial for the treatment of canine aggression, and stereotypic or other obsessive-compulsive behaviors. It has been used occasionally in cats as well.
Paroxetine Preparation Products And Raw materials
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