🧬 Receptor activity
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Sodium-dependent serotonin transporter | — | Ki 0.05 nM | CHEMBL | TargetSodium-dependent serotonin transporter Action— AffinityKi 0.05 nM SourceCHEMBL |
| Transporter | — | Ki 59 nM | CHEMBL | TargetTransporter Action— AffinityKi 59 nM SourceCHEMBL |
| Sodium-dependent dopamine transporter | — | Ki 98 nM | CHEMBL | TargetSodium-dependent dopamine transporter Action— AffinityKi 98 nM SourceCHEMBL |
| Unchecked | — | Ki 2000 nM | CHEMBL | TargetUnchecked Action— AffinityKi 2000 nM SourceCHEMBL |
Mechanism of action
Paroxetine enhances serotonergic activity via the inhibition presynaptic reuptake of serotonin by the serotonin (SERT) receptor. This inhibition raises the level of serotonin in the synaptic cleft, relieving various symptoms. This drug has been demonstrated to be a stronger inhibitor of serotonin reuptake than other members of the same drug class, including [Citalopram], [Fluoxetine], and [Fluvoxamine]. The mechanism of action of paroxetine in relieving the vasomotor symptoms of menopause is unknown, according to the Brisdelle prescribing information, but may occur due to its effects on thermoregulation. Paroxetine shows a clinically insignificant affinity for adrenergic alpha-1 and alpha-2 receptors and β-adrenergic receptors, dopamine D1 and D2 receptors, histamine H1 receptors and serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors. This drug shows some affinity for muscarinic cholinergic receptors and 5-H2B receptors. The delayed onset of paroxetine therapeutic effects may be explained by the initial paroxetine actions on the 5-HT neurons. In rats, paroxetine activates 5-HT1A receptors when it is first administered, inhibiting the stimulation of the 5-HT neurons and subsequent release of serotonin at the synaptic cleft.
Functional and structural approaches were used to examine the inhibitory mechanisms and binding site location for fluoxetine and paroxetine, two serotonin selective reuptake inhibitors, on nicotinic acetylcholine receptors (AChRs) in different conformational states. The results establish that: (a) fluoxetine and paroxetine inhibit h alpha1beta1 gammadelta AChR-induced Ca(2+) influx with higher potencies than dizocilpine. The potency of fluoxetine is increased approximately 10-fold after longer pre-incubation periods, which is in agreement with the enhancement of (3)H-cytisine binding to resting but activatable Torpedo AChRs elicited by these antidepressants, (b) fluoxetine and paroxetine inhibit the binding of the phencyclidine analog piperidyl-3,4-(3)H(N)]-(N-(1-(2 thienyl)cyclohexyl)-3,4-piperidine to the desensitized Torpedo AChR with higher affinities compared to the resting AChR, and (c) fluoxetine inhibits (3)H-dizocilpine binding to the desensitized AChR, suggesting a mutually exclusive interaction. This is supported by our molecular docking results where neutral dizocilpine and fluoxetine and the conformer of protonated fluoxetine with the highest LUDI score interact with the domain between the valine (position 13') and leucine (position 9') rings. Molecular mechanics calculations also evidence electrostatic interactions of protonated fluoxetine at positions 20', 21', and 24'. Protonated dizocilpine bridges these two binding domains by interacting with the valine and outer (position 20') rings. The high proportion of protonated fluoxetine and dizocilpine calculated at physiological pH suggests that the protonated drugs can be attracted to the channel mouth before binding deeper within the AChR ion channel between the leucine and valine rings, a domain shared with phencyclidine, finally blocking ion flux and inducing AChR desensitization.
Paroxetine was shown to be a potent (Ki = 1.1 nM) and specific inhibitor of [3H]-5-hydroxytryptamine (5-HT) uptake into rat cortical and hypothalamic synaptosomes in vitro. Lineweaver-Burk kinetic analysis determined that this inhibition was competitive in nature, implying a direct interaction with the 5-HT uptake transporter complex. Oral administration of paroxetine produced a dose-related inhibition of [3H]-5-HT uptake (ED50 = 1.9 mg/kg) into rat hypothalamic synaptosomes ex vivo with little effect on [3H]-l-noradrenaline (NA) uptake (ED50 greater than 30 mg/kg). This selectivity for 5-HT uptake was maintained after oral dosing for 14 days. Paroxetine (ED50 1-3 mg/kg PO) prevented the 5-HT depleting effect of p-chloroamphetamine (PCA) in rat brain, demonstrating 5-HT uptake blockade in vivo. Radioligand binding techniques in rat brain in vitro showed that paroxetine has little affinity for alpha 1, alpha 2 or beta adrenoceptors, dopamine (D2), 5-HT1, 5-HT2 or histamine (H1) receptors at concentrations below 1000 nM. Paroxetine demonstrated weak affinity for muscarinic receptors (Ki = 89 nM) but was at least 15 fold weaker than amitriptyline (Ki = 5.1 nM). Paroxetine, therefore, provides a useful pharmacological tool for investigating 5-HT systems and furthermore should be an antidepressant with reduced tricyclic-like side-effects.
The precise mechanism of antidepressant action of paroxetine is unclear, but the drug has been shown to selectively inhibit the reuptake of serotonin at the presynaptic neuronal membrane. Paroxetine-induced inhibition of serotonin reuptake causes increased synaptic concentrations of serotonin in the CNS, resulting in numerous functional changes associated with enhanced serotonergic neurotransmission. Like other SSRIs (e.g., citalopram, fluoxetine, fluvoxamine, sertraline), paroxetine appears to have only very weak effects on the reuptake of norepinephrine or dopamine and does not exhibit clinically important anticholinergic, antihistaminic, or adrenergic (a1, a2, beta) blocking activity at usual therapeutic dosages. Although the mechanism of antidepressant action of antidepressant agents may involve inhibition of the reuptake of various neurotransmitters (i.e., serotonin, norepinephrine) at the presynaptic neuronal membrane, it has been suggested that postsynaptic receptor modification is mainly responsible for the antidepressant action observed during long-term administration of antidepressant agents. During long-term therapy with most antidepressants (e.g., tricyclic antidepressants, monoamine oxidase (MAO) inhibitors), these adaptive changes mainly consist of subsensitivity of the noradrenergic adenylate cyclase system in association with a decrease in the number of beta-adrenergic receptors; such effects on noradrenergic receptor function are commonly referred to as down regulation. However, in an animal study, long-term administration of paroxetine was not shown to downregulate noradrenergic receptors in the CNS as has been observed with many other clinically effective antidepressants. In addition, some antidepressants (e.g., amitriptyline) reportedly decrease the number of serotonergic (5-HT) binding sites following chronic administration.
Reduced glucose metabolism has been implicated as a pathophysiology of depressive disorder. Normalization of such impaired neurometabolism has been related to the therapeutic actions of antidepressant medication. However, the molecular mechanism underlying the neurometabolic actions of antidepressants has not been fully understood. Given that AMP-activated protein kinase (AMPK) is a master switch for energy homeostasis, we aimed to determine whether selective serotonin reuptake inhibitor paroxetine enhances energy metabolism by activating AMPK in neuroblastoma cells. We found that paroxetine dose dependently increased mitochondrial biogenesis, which involves the AMPK-peroxisome proliferator-activated receptor-gamma coactivator-1a pathway. In addition, paroxetine-induced AMPK activation increases glucose uptake and ATP production. These neurometabolic effects of paroxetine were suppressed by cotreatment with compound C (CC), an AMPK inhibitor. These findings suggest a possibility that modulation of the AMPK pathway might be a previously unrecognized mechanism underlying the neurometabolic action of antidepressants. Further study is warranted to examine the region-specific and time-specific effects of AMPK modulation by antidepressants on mood-related behaviors.
For more Mechanism of Action (Complete) data for PAROXETINE (9 total), please visit the HSDB record page.
Pharmacodynamics
Paroxetine treats the symptoms of depression, various anxiety disorders, posttraumatic stress disorder, obsessive-compulsive disorder, and the vasomotor symptoms of menopause via the inhibition of serotonin reuptake. The onset of action of paroxetine is reported to be approximately 6 weeks. Due its serotonergic activity, paroxetine, like other SSRI drugs, may potentiate serotonin syndrome. This risk is especially high when monoamine oxidase (MAO) inhibitors are given within 2 weeks of paroxetine administration. Upon cessation of MAO inhibitors, a 2-week interval before paroxetine administration is recommended. Do not coadminister these agents.
Pharmacokinetics
Half-life
The mean elimination half-life of paroxetine is about 21 hours. In healthy young subjects, mean elimination half-life was found to be 17.3 hours.
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean ... half life was ... 21.0 hours (CV 32%) ... .
The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of Paxil.
The elimination half-life of paroxetine when administered as paroxetine hydrochloride averages approximately 21-24 hours, although there is wide interpatient variation with half-lives (ranging from 7-65 hours in one study). In healthy males receiving one 30-mg tablet of paroxetine (administered as paroxetine mesylate) once daily for 24 days, the mean paroxetine half-life was 33.2 hours. In geriatric individuals, elimination half-life of paroxetine (administered as paroxetine hydrochloride) may be increased (e.g., to about 36 hours).
Absorption
Paroxetine is readily absorbed from the gastrointestinal tract. Due to the first-pass metabolism, the bioavailability ranges from 30-60%. Cmax is attained 2 to 8 hours after an oral dose. Mean Tmax is 4.3 hours in healthy patients. The steady-state concentration of paroxetine is achieved within 7 to 14 days of oral therapy. In a pharmacokinetic study, AUC in healthy patients was 574 ng·h/mL and 1053 ng·h/mL in those with moderate renal impairment.
About 2/3 of a single paroxetine dose is found to be excreted in the urine and the remainder is found to be excreted in feces. Almost all of the dose is eliminated as metabolites; 3% is found to be excreted as unchanged paroxetine. About 64% of a 30 mg oral dose was found excreted in the urine, with 2% as the parent drug and 62% appearing as metabolites. Approximately 36% of the dose was found to be eliminated in the feces primarily as metabolites and less than 1% as the parent compound.
Paroxetine has a large volume of distribution and is found throughout the body, including in the central nervous system. Only 1% of the drug is found in the plasma. Paroxetine is found in the breast milk at concentrations similar to the concentrations found in plasma.
The apparent oral clearance of paroxetine is 167 L/h. The clearance of paroxetine in patients with renal failure is significantly lower and dose adjustment may be required, despite the fact that it is mainly cleared by the liver. Dose adjustments may be required in hepatic impairment.
Paroxetine hydrochloride appears to be slowly but well absorbed from the GI tract following oral administration. Although the oral bioavailability of paroxetine hydrochloride in humans has not been fully elucidated to date, the manufacturer states that paroxetine is completely absorbed after oral dosing of a solution of the hydrochloride salt. However, the relative proportion of an oral dose that reaches systemic circulation unchanged appears to be relatively small because paroxetine undergoes extensive first-pass metabolism. The oral tablets and suspension of paroxetine hydrochloride reportedly are bioequivalent.
In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled.
Metabolism
Paroxetine metabolism occurs in the liver and is largely mediated by cytochrome CYP2D6 with contributions from CYP3A4 and possibly other cytochrome enzymes. Genetic polymorphisms of the CYP2D6 enzyme may alter the pharmacokinetics of this drug. Poor metabolizers may demonstrate increased adverse effects while rapid metabolizers may experience decreased therapeutic effects. The majority of a paroxetine dose is oxidized to a catechol metabolite that is subsequently converted to both glucuronide and sulfate metabolites via methylation and conjugation. In rat synaptosomes, the glucuronide and sulfate conjugates have been shown to thousands of times less potent than paroxetine itself. The metabolites of paroxetine are considered inactive.
The exact metabolic fate of paroxetine has not been fully elucidated; however, paroxetine is extensively metabolized, probably in the liver. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared by the body. Conjugates with glucuronic acid and sulfate predominate, and the principal metabolites have been isolated and identified. The metabolites of paroxetine have been shown to possess no more than 2% of the potency of the parent compound as inhibitors of serotonin reuptake; therefore, they are essentially inactive.
Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions
Paroxetine has known human metabolites that include 4-[[(3S,4R)-4-(4-Fluorophenyl)piperidin-3-yl]methoxy]benzene-1,2-diol.
Paroxetine is extensively metabolized after oral administration, likely in the liver. The main metabolites are polar and conjugated products of oxidation and methylation, which are readily eliminated by the body. The predominant metabolites are glucuronic acid and sulfate conjugates. Paroxetine metabolites do not possess significant pharmacologic activity (less than 2% that of parent compound). Paroxetine is metabolized by cytochrome P450 (CYP) 2D6. Enzyme saturation appears to account for the nonlinear pharmacokinetics observed with increasing dose and duration of therapy.
Route of Elimination: Approximately 64% of a 30 mg oral solution of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites. Approximately 36% of the dose was excreted in the feces (via bile), mostly as metabolites and less than 1% as parent compound.
Half Life: 21-24 hours
Protein binding
Paroxetine is 95% bound to plasma proteins.
External links
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