Collated from TripSit, Pharmacology, DrugCentral, DailyMed. Where sources differ (e.g. dosing), Compare shows them side by side.
Also known as prozac, sarafemTS
🧬 Receptor activityPHDC
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Sodium-dependent serotonin transporter | — | Ki 1.1 nM | CHEMBL | TargetSodium-dependent serotonin transporter Action— AffinityKi 1.1 nM SourceCHEMBL |
| 5-hydroxytryptamine receptor 2C | — | Ki 72 nM | CHEMBL | Target5-hydroxytryptamine receptor 2C Action— AffinityKi 72 nM SourceCHEMBL |
| Unchecked | — | Ki 392 nM | CHEMBL | TargetUnchecked Action— AffinityKi 392 nM SourceCHEMBL |
| Transporter | — | Ki 473 nM | CHEMBL | TargetTransporter Action— AffinityKi 473 nM SourceCHEMBL |
| Sodium-dependent dopamine transporter | — | Ki 784 nM | CHEMBL | TargetSodium-dependent dopamine transporter Action— AffinityKi 784 nM SourceCHEMBL |
| 5-hydroxytryptamine receptor 2A (Htr2a) | Antagonist | 6.5 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 2A (Htr2a) ActionAntagonist Affinity6.5 Ki SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 2B (HTR2B) | Antagonist | 5.3 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 2B (HTR2B) ActionAntagonist Affinity5.3 Ki SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 6 (Htr6) | Antagonist | 5.8 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 6 (Htr6) ActionAntagonist Affinity5.8 Ki SourceDRUGCENTRAL |
| Equilibrative nucleoside transporter 4 (SLC29A4) | Inhibitor | 4.64 Ki | DRUGCENTRAL | TargetEquilibrative nucleoside transporter 4 (SLC29A4) ActionInhibitor Affinity4.64 Ki SourceDRUGCENTRAL |
| G protein-activated inward rectifier potassium channel 2 (Kcnj6) | Gating inhibitor | 4.8 IC50 | DRUGCENTRAL | TargetG protein-activated inward rectifier potassium channel 2 (Kcnj6) ActionGating inhibitor Affinity4.8 IC50 SourceDRUGCENTRAL |
| Sodium-dependent serotonin transporter (SLC6A4) | Inhibitor | 9.091 Kd | DRUGCENTRAL | TargetSodium-dependent serotonin transporter (SLC6A4) ActionInhibitor Affinity9.091 Kd SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 2A (HTR2A) | — | 6.61 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 2A (HTR2A) Action— Affinity6.61 Ki SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 2C (HTR2C) | — | 6.4 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 2C (HTR2C) Action— Affinity6.4 Ki SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 6 (HTR6) | — | 6.11 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 6 (HTR6) Action— Affinity6.11 Ki SourceDRUGCENTRAL |
| Acetylcholinesterase (ACHE) | — | 6.89 IC50 | DRUGCENTRAL | TargetAcetylcholinesterase (ACHE) Action— Affinity6.89 IC50 SourceDRUGCENTRAL |
| Adrenergic receptor alpha-1 (Adra1b) | — | 6.22 Ki | DRUGCENTRAL | TargetAdrenergic receptor alpha-1 (Adra1b) Action— Affinity6.22 Ki SourceDRUGCENTRAL |
| Adrenergic receptor alpha-2 (Adra2b) | — | 5.72 Ki | DRUGCENTRAL | TargetAdrenergic receptor alpha-2 (Adra2b) Action— Affinity5.72 Ki SourceDRUGCENTRAL |
| Alpha-1A adrenergic receptor (ADRA1A) | — | 5.699 Ki | DRUGCENTRAL | TargetAlpha-1A adrenergic receptor (ADRA1A) Action— Affinity5.699 Ki SourceDRUGCENTRAL |
| Alpha-2A adrenergic receptor (ADRA2A) | — | 8.2 Ki | DRUGCENTRAL | TargetAlpha-2A adrenergic receptor (ADRA2A) Action— Affinity8.2 Ki SourceDRUGCENTRAL |
| Alpha-2B adrenergic receptor (ADRA2B) | — | 6.156 Ki | DRUGCENTRAL | TargetAlpha-2B adrenergic receptor (ADRA2B) Action— Affinity6.156 Ki SourceDRUGCENTRAL |
| Beta-1 adrenergic receptor (ADRB1) | — | 5.356 Ki | DRUGCENTRAL | TargetBeta-1 adrenergic receptor (ADRB1) Action— Affinity5.356 Ki SourceDRUGCENTRAL |
| Cytochrome P450 2D6 (CYP2D6) | — | 6.155 IC50 | DRUGCENTRAL | TargetCytochrome P450 2D6 (CYP2D6) Action— Affinity6.155 IC50 SourceDRUGCENTRAL |
| D(3) dopamine receptor (DRD3) | — | 5.699 Ki | DRUGCENTRAL | TargetD(3) dopamine receptor (DRD3) Action— Affinity5.699 Ki SourceDRUGCENTRAL |
| Histamine H1 receptor (HRH1) | — | 5.959 Ki | DRUGCENTRAL | TargetHistamine H1 receptor (HRH1) Action— Affinity5.959 Ki SourceDRUGCENTRAL |
| Histamine H3 receptor (HRH3) | — | 5.14 Ki | DRUGCENTRAL | TargetHistamine H3 receptor (HRH3) Action— Affinity5.14 Ki SourceDRUGCENTRAL |
| Muscarinic acetylcholine receptor M1 (CHRM1) | — | 6.047 Ki | DRUGCENTRAL | TargetMuscarinic acetylcholine receptor M1 (CHRM1) Action— Affinity6.047 Ki SourceDRUGCENTRAL |
| Muscarinic acetylcholine receptor M2 (CHRM2) | — | 5.569 Ki | DRUGCENTRAL | TargetMuscarinic acetylcholine receptor M2 (CHRM2) Action— Affinity5.569 Ki SourceDRUGCENTRAL |
| Muscarinic acetylcholine receptor M3 (CHRM3) | — | 6 Ki | DRUGCENTRAL | TargetMuscarinic acetylcholine receptor M3 (CHRM3) Action— Affinity6 Ki SourceDRUGCENTRAL |
| Muscarinic acetylcholine receptor M4 (CHRM4) | — | 5.538 Ki | DRUGCENTRAL | TargetMuscarinic acetylcholine receptor M4 (CHRM4) Action— Affinity5.538 Ki SourceDRUGCENTRAL |
| Muscarinic acetylcholine receptor M5 (CHRM5) | — | 5.569 Ki | DRUGCENTRAL | TargetMuscarinic acetylcholine receptor M5 (CHRM5) Action— Affinity5.569 Ki SourceDRUGCENTRAL |
| Potassium channel subfamily K member 2 (KCNK2) | — | 4.85 IC50 | DRUGCENTRAL | TargetPotassium channel subfamily K member 2 (KCNK2) Action— Affinity4.85 IC50 SourceDRUGCENTRAL |
| Potassium voltage-gated channel subfamily C member 1 (Kcnc1) | — | 4.88 IC50 | DRUGCENTRAL | TargetPotassium voltage-gated channel subfamily C member 1 (Kcnc1) Action— Affinity4.88 IC50 SourceDRUGCENTRAL |
| Potassium voltage-gated channel subfamily H member 2 (KCNH2) | — | 6.155 IC50 | DRUGCENTRAL | TargetPotassium voltage-gated channel subfamily H member 2 (KCNH2) Action— Affinity6.155 IC50 SourceDRUGCENTRAL |
| Serotonin 1 (5-HT1) receptor (Htr1a) | — | 7.82 IC50 | DRUGCENTRAL | TargetSerotonin 1 (5-HT1) receptor (Htr1a) Action— Affinity7.82 IC50 SourceDRUGCENTRAL |
| Sigma non-opioid intracellular receptor 1 (SIGMAR1) | — | 6.07 IC50 | DRUGCENTRAL | TargetSigma non-opioid intracellular receptor 1 (SIGMAR1) Action— Affinity6.07 IC50 SourceDRUGCENTRAL |
| Sodium-dependent dopamine transporter (SLC6A3) | — | 5.444 Kd | DRUGCENTRAL | TargetSodium-dependent dopamine transporter (SLC6A3) Action— Affinity5.444 Kd SourceDRUGCENTRAL |
| Sodium-dependent noradrenaline transporter (SLC6A2) | — | 6.62 Kd | DRUGCENTRAL | TargetSodium-dependent noradrenaline transporter (SLC6A2) Action— Affinity6.62 Kd SourceDRUGCENTRAL |
| Sodium-dependent serotonin transporter (Slc6a4) | — | 8.7 Ki | DRUGCENTRAL | TargetSodium-dependent serotonin transporter (Slc6a4) Action— Affinity8.7 Ki SourceDRUGCENTRAL |
| Transporter (Slc6a2) | — | 6.84 Ki | DRUGCENTRAL | TargetTransporter (Slc6a2) Action— Affinity6.84 Ki SourceDRUGCENTRAL |
Mechanism of actionPHDM
The monoaminergic hypothesis of depression emerged in 1965 and linked depression with dysfunction of neurotransmitters such as noradrenaline and serotonin. Indeed, low levels of serotonin have been observed in the cerebrospinal fluid of patients diagnosed with depression. As a result of this hypothesis, drugs that modulate levels of serotonin such as fluoxetine were developed. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and as the name suggests, it exerts it's therapeutic effect by inhibiting the presynaptic reuptake of the neurotransmitter serotonin. As a result, levels of 5-hydroxytryptamine (5-HT) are increased in various parts of the brain. Further, fluoxetine has high affinity for 5-HT transporters, weak affinity for noradrenaline transporters and no affinity for dopamine transporters indicating that it is 5-HT selective. Fluoxetine interacts to a degree with the 5-HT<sub>2C</sub> receptor and it has been suggested that through this mechanism, it is able to increase noradrenaline and dopamine levels in the prefrontal cortex.
PharmacodynamicsPHDM
Fluoxetine blocks the serotonin reuptake transporter in the presynaptic terminal, which ultimately results in sustained levels of 5-hydroxytryptamine (5-HT) in certain brain areas. However, fluoxetine binds with relatively poor affinity to 5-HT, dopaminergic, adrenergic, cholinergic, muscarinic, and histamine receptors which explains why it has a far more desirable adverse effect profile compared to earlier developed classes of antidepressants such as tricyclic antidepressants.
Pharmacokinetics
Half-lifePH
The half life of fluoxetine is significant with the elimination half-life of the parent drug averaging 1-3 days after acute administration, and 4-6 days after chronic administration. Further, the elimination half life of it's active metabolite, norfluoxetine, ranges from 4-16 days after both acute and chronic administration. The half-life of fluoxetine should be considered when switching patients from fluoxetine to another antidepressant since marked accumulation occurs after chronic use. Fluoxetine's long half-life may even be beneficial when discontinuing the drug since the risk of withdrawal is minimized.
AbsorptionPHDM
The oral bioavailability of fluoxetine is <90% as a result of hepatic first pass metabolism. In a bioequivalence study, the Cmax of fluoxetine 20 mg for the established reference formulation was 11.754 ng/mL while the Cmax for the proposed generic formulation was 11.786 ng/ml. Fluoxetine is very lipophilic and highly plasma protein bound, allowing the drug and it's active metabolite, norfluoxetine, to be distributed to the brain.
Fluoxetine is primarily eliminated in the urine.
The volume of distribution of fluoxetine and it's metabolite varies between 20 to 42 L/kg.
The clearance value of fluoxetine in healthy patients is reported to be 9.6 ml/min/kg.
MetabolismPH
Fluoxetine is metabolized to norfluoxetine by CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 upon ingestion. Although all of the mentioned enzymes contribute to N-demethylation of fluoxetine, CYP2D6, CYP2C9 and CYP3A4 appear to be the major contributing enzymes for phase I metabolism. In addition, there is evidence to suggest that CYP2C19 and CYP3A4 mediate O-dealkylation of fluoxetine and norfluoxetine to produce para-trifluoromethylphenol which is subsequently metabolized to hippuric acid. Both fluoxetine and norfluoxetine undergo glucuronidation to facilitate excretion. Notably, both the parent drug and active metabolite inhibit CYP2D6 isozymes, and as a result patients who are being treated with fluoxetine are susceptible to drug interactions.
Fluoxetine has known human metabolites that include Norfluoxetine, p-Trifluoromethyl phenol, and (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[methyl-[3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl]amino]oxane-2-carboxylic acid.
Limited data from animal studies suggest that fluoxetine may undergo first-pass metabolism may occur via the liver and/or lungs. Fluoxetine appears to be extensively metabolized, likely in the liver, to norfluoxetine and other metabolites. Norfluoxetine, the principal active metabolite, is formed via <i>N</i>-demethylation of fluoxetine. Norfluoxetine appears to be comparable pharmacologic potency as fluoxetine. Fluoxetine and norfluoxetine both undergo phase II glucuronidation reactions in the liver. It is also thought that fluoxetine and norfluoxetine undergo <i>O</i>-dealkylation to form <i>p</i>-trifluoromethylphenol, which is then subsequently metabolized to hippuric acid.
Route of Elimination: The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. The S-enantiomer is eliminated more slowly and is the predominant enantiomer present at steady state.
Half Life: 1-3 days [acute administration];
4-6 days [chronic administration];
4-16 days [norfluoxetine, acute and chronic administration].
Protein bindingPH
Approximately 94% of fluoxetine is plasma protein bound.
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.