Fenfluramine
Identification
- Summary
Fenfluramine is fenfluramine is a phenethylamine that is structurally similar to serotonin. Due to its ability to increase extracellular serotonin levels, modulate serotonergic and other neurologic receptors, and control neurotransmission, it is effective in treating pharmacoresistant seizures.
- Brand Names
- Fintepla
- Generic Name
- Fenfluramine
- DrugBank Accession Number
- DB00574
- Background
Dravet syndrome is a pediatric encephalopathy that typically manifests within the first year of life following exposure to elevated temperatures. It is characterized by recurrent pharmacoresistant seizures, which increase in frequency and severity with disease progression. Concomitantly with these seizures, patients typically display delayed development and neurocognitive impairment.6,9,10,11 Fenfluramine is a serotonergic phenethylamine originally used as an appetite suppressant until concerns regarding cardiotoxicity in obese patients lead to its withdrawal from the market in 1997.6,12,13 Through its ability to modulate neurotransmission, fenfluramine has reemerged as an effective therapy against pharmacoresistant seizures, such as those involved in Dravet syndrome.3,5,8
Fenfluramine was granted initial FDA approval in 1973 prior to its withdrawal; it was granted a new FDA approval on June 25, 2020, for treatment of patients with Dravet syndrome and Lennox-Gastaut syndrome through the restricted FINTEPLA REMS program. It is currently sold under the name FINTEPLA® by Zogenix INC.16
- Type
- Small Molecule
- Groups
- Approved, Illicit, Investigational, Withdrawn
- Structure
- Weight
- Average: 231.2573
Monoisotopic: 231.123484132 - Chemical Formula
- C12H16F3N
- Synonyms
- (±)-fenfluramine
- 1-(m-trifluoromethyl-phenyl)-2-ethylaminopropane
- DL-Fenfluramine
- Fenfluramina
- Fenfluramine
- Fenfluraminum
- External IDs
- DEA No. 1670
- S 768
Pharmacology
- Indication
Fenfluramine is indicated for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome in patients aged two years and older.16
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- Pharmacodynamics
Fenfluramine increases extracellular serotonin levels, and also acts as both a serotonergic 5-HT2 receptor agonist and σ1 receptor antagonist. These activities, through an incompletely understood mechanism, lead to anti-epileptiform activity and therapeutic benefit.1,2,3,4,5,6,7,8,16 This modulation has other effects such as decreased appetite, weight loss, sedation, lethargy, increased blood pressure, and mood alteration including possible suicidal ideation. There is a risk of glaucoma and potentially fatal serotonin syndrome. Fenfluramine should be gradually withdrawn following treatment alteration or cessation.16
- Mechanism of action
Dravet syndrome is a complex pediatric encephalopathy characterized by recurrent pharmacoresistant seizures of variable type, delayed development, and in many cases, impairment in speech, language, gait, and other neurocognitive functions.6,9,10,11 Despite substantial variation in presentation and severity, roughly 80% of patients with Dravet syndrome have mutations in the SCN1A gene, which encodes the alpha subunit of a voltage-gated sodium channel (Nav1.1).2,3,5,8,9,11 This channel is predominantly localized in inhibitory GABAergic interneurons as well as in excitatory pyramidal neurons; it is thought that dysfunction of neurotransmission regulation results in the seizures and other corresponding symptoms of Dravet syndrome.8,9
Various in vitro and in vivo studies have demonstrated that fenfluramine is capable of acting as an agonist of multiple serotonin receptors including 5-HT1A, 5-HT1D, 5-HT2A, 5-HT2B, and 5-HT2C, as well as a σ1 receptor antagonist.1,2,3,4,5,6,7,8,16 This is at least partly because fenfluramine, as well as its active metabolite norfenfluramine, can act on sodium-dependent serotonin transporters (SERTs) to reverse transport direction and thereby increase extracellular serotonin levels.14,15 However, work in animal models of Dravet syndrome suggest that only the modulation of 5-HT1D, 5-HT2C, σ1, and possibly 5-HT2A receptors of fenfluramine result in the anti-epileptiform activity.3,5,8 Interestingly, 5-HT2B receptor agonism, which had previously been associated with cardiac valvulopathy,12,13 is not anticipated to have any therapeutic value in Dravet syndrome.8
Although the exact mechanism by which stimulation/inhibition of various receptors leads to the observed therapeutic benefit is unclear, it is hypothesized to be two-fold. Stimulation of 5-HT1D and 5-HT2C may result in increased GABAergic neurotransmission, while σ1 receptor antagonism may help to modulate responses to N-methyl-D-aspartate (NMDA).8
Target Actions Organism ASodium-dependent serotonin transporter substrateinhibitorHumans A5-hydroxytryptamine receptor 1D agonistHumans A5-hydroxytryptamine receptor 2C agonistHumans ASigma non-opioid intracellular receptor 1 antagonistHumans U5-hydroxytryptamine receptor 2A agonistHumans N5-hydroxytryptamine receptor 2B agonistHumans N5-hydroxytryptamine receptor 1A agonistHumans - Absorption
Fenfluramine has a steady-state Tmax of between four and five hours and an absolute bioavailability of approximately 68-74%. Fenfluramine administered to pediatric patients at 0.7 mg/kg/day up to 26 mg resulted in a mean Cmax of 68.0 ng/mL with a coefficient of variation of 41%; similarly the AUC0-24 was 1390 (44%) ng*h/mL.16
- Volume of distribution
Fenfluramine has an apparent volume of distribution of 11.9 L/kg with a coefficient of variation of 16.5% following oral administration in healthy subjects.16
- Protein binding
Fenfluramine is 50% bound to plasma proteins independent of plasma drug concentration.16
- Metabolism
Fenfluramine is metabolized primarily in the liver by CYP1A2, CYP2B6, CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 to yield the major active metabolite norfenfluramine and several other minor inactive metabolites.16
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- Route of elimination
Over 90% of fenfluramine is excreted in urine and less than 5% in feces; unchanged fenfluramine and the major active metabolite norfenfluramine account for less than 25% of the recovered amount.16
- Half-life
Fenfluramine has an elimination half-life of 20 hours in healthy subjects.16
- Clearance
Fenfluramine has a mean clearance of 24.8 L/h with a coefficient of variation of 29% in healthy subjects.16
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
Overdosage of fenfluramine has been reported; in overdose cases, symptoms include agitation, anxiety, restlessness, twitching, tremors/muscle spasms, flushing, tachycardia, mydriasis, increased muscle tone, respiratory distress/failure, seizure, and coma. Some overdosage cases proved fatal, and in most fatal cases, patients experienced seizures, coma, and cardiorespiratory arrest.16
There is currently no standard practice for managing fenfluramine overdose. Symptomatic management, including ensuring proper ventilation and monitoring of both cardiac and respiratory functions is recommended.16
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of CNS depression can be increased when Fenfluramine is combined with 1,2-Benzodiazepine. Abametapir The serum concentration of Fenfluramine can be increased when it is combined with Abametapir. Abatacept The metabolism of Fenfluramine can be increased when combined with Abatacept. Abiraterone The serum concentration of Fenfluramine can be increased when it is combined with Abiraterone. Acebutolol The metabolism of Acebutolol can be decreased when combined with Fenfluramine. - Food Interactions
- Take with or without food. The absorption is unaffected by food.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Fenfluramine hydrochloride 3KC089243P 404-82-0 ZXKXJHAOUFHNAS-UHFFFAOYSA-N - International/Other Brands
- Adifax / Obedrex / Ponderax / Ponderax PA / Pondimin / Rotondin
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Fintepla Solution 2.2 mg/ml Oral Ucb Pharma S.A. 2021-01-12 Not applicable EU Fintepla Solution 2.2 mg/ml Oral Ucb Pharma S.A. 2021-01-12 Not applicable EU Fintepla Solution 2.2 mg/ml Oral Ucb Pharma S.A. 2021-01-12 Not applicable EU Fintepla Solution 2.2 mg/1mL Oral UCB, Inc. 2020-07-15 Not applicable US Fintepla Solution 2.2 mg/ml Oral Ucb Pharma S.A. 2021-01-12 Not applicable EU
Categories
- ATC Codes
- A08AA02 — Fenfluramine
- A08AA — Centrally acting antiobesity products
- A08A — ANTIOBESITY PREPARATIONS, EXCL. DIET PRODUCTS
- A08 — ANTIOBESITY PREPARATIONS, EXCL. DIET PRODUCTS
- A — ALIMENTARY TRACT AND METABOLISM
- Drug Categories
- Alimentary Tract and Metabolism
- Amines
- Anticonvulsants
- Antidepressive Agents
- Antiobesity Preparations, Excl. Diet Products
- Central Nervous System Depressants
- Centrally Acting Antiobesity Products
- Cytochrome P-450 CYP1A2 Substrates
- Cytochrome P-450 CYP2B6 Substrates
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP2D6 Inhibitors
- Cytochrome P-450 CYP2D6 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Ethylamines
- Membrane Transport Modulators
- Nervous System
- Neurotransmitter Agents
- Neurotransmitter Uptake Inhibitors
- Phenethylamines
- Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
- Serotonin 5-HT2 Receptor Agonists
- Serotonin Agents
- Serotonin Receptor Agonists
- Stimulants
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as amphetamines and derivatives. These are organic compounds containing or derived from 1-phenylpropan-2-amine.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Phenethylamines
- Direct Parent
- Amphetamines and derivatives
- Alternative Parents
- Trifluoromethylbenzenes / Phenylpropanes / Aralkylamines / Dialkylamines / Organopnictogen compounds / Organofluorides / Hydrocarbon derivatives / Alkyl fluorides
- Substituents
- Alkyl fluoride / Alkyl halide / Amine / Amphetamine or derivatives / Aralkylamine / Aromatic homomonocyclic compound / Hydrocarbon derivative / Organic nitrogen compound / Organofluoride / Organohalogen compound
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- secondary amino compound, (trifluoromethyl)benzenes (CHEBI:5000)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 2DS058H2CF
- CAS number
- 458-24-2
- InChI Key
- DBGIVFWFUFKIQN-UHFFFAOYSA-N
- InChI
- InChI=1S/C12H16F3N/c1-3-16-9(2)7-10-5-4-6-11(8-10)12(13,14)15/h4-6,8-9,16H,3,7H2,1-2H3
- IUPAC Name
- ethyl({1-[3-(trifluoromethyl)phenyl]propan-2-yl})amine
- SMILES
- CCNC(C)CC1=CC=CC(=C1)C(F)(F)F
References
- Synthesis Reference
Vincenzo Cannata, Barbara Galbiati, Angelo Spreafico, "Process for manufacturing 1-(3-trifluoromethyl)-phenyl-propan-2-one intermediate in the synthesis of the fenfluramine." U.S. Patent US5811586, issued August, 1965.
US5811586- General References
- Fuller RW, Snoddy HD, Robertson DW: Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats: uptake inhibition versus release. Pharmacol Biochem Behav. 1988 Jul;30(3):715-21. doi: 10.1016/0091-3057(88)90089-5. [Article]
- Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC: Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome. Brain. 2017 Mar 1;140(3):669-683. doi: 10.1093/brain/aww342. [Article]
- Martin P, de Witte PAM, Maurice T, Gammaitoni A, Farfel G, Galer B: Fenfluramine acts as a positive modulator of sigma-1 receptors. Epilepsy Behav. 2020 Apr;105:106989. doi: 10.1016/j.yebeh.2020.106989. Epub 2020 Mar 10. [Article]
- Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ: Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol. 1999 Sep;128(1):13-20. [Article]
- Rodriguez-Munoz M, Sanchez-Blazquez P, Garzon J: Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget. 2018 May 4;9(34):23373-23389. doi: 10.18632/oncotarget.25169. eCollection 2018 May 4. [Article]
- Schoonjans AS, Ceulemans B: An Old Drug for a New Indication: Repurposing Fenfluramine From an Anorexigen to an Antiepileptic Drug. Clin Pharmacol Ther. 2019 Nov;106(5):929-932. doi: 10.1002/cpt.1469. Epub 2019 May 22. [Article]
- Sourbron J, Schneider H, Kecskes A, Liu Y, Buening EM, Lagae L, Smolders I, de Witte P: Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model. ACS Chem Neurosci. 2016 May 18;7(5):588-98. doi: 10.1021/acschemneuro.5b00342. Epub 2016 Feb 17. [Article]
- Sourbron J, Smolders I, de Witte P, Lagae L: Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish. Front Pharmacol. 2017 Apr 6;8:191. doi: 10.3389/fphar.2017.00191. eCollection 2017. [Article]
- Gataullina S, Dulac O: From genotype to phenotype in Dravet disease. Seizure. 2017 Jan;44:58-64. doi: 10.1016/j.seizure.2016.10.014. Epub 2016 Oct 21. [Article]
- Gonzalez-Giraldo E, Sullivan JE: Advances in the Treatment of Drug-Resistant Pediatric Epilepsy. Semin Neurol. 2020 Apr;40(2):257-262. doi: 10.1055/s-0040-1702941. Epub 2020 Mar 17. [Article]
- Wheless JW, Fulton SP, Mudigoudar BD: Dravet Syndrome: A Review of Current Management. Pediatr Neurol. 2020 Jun;107:28-40. doi: 10.1016/j.pediatrneurol.2020.01.005. Epub 2020 Jan 31. [Article]
- Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV: Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997 Aug 28;337(9):581-8. doi: 10.1056/NEJM199708283370901. [Article]
- Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL: Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000 Dec 5;102(23):2836-41. [Article]
- Rothman RB, Baumann MH, Blough BE, Jacobson AE, Rice KC, Partilla JS: Evidence for noncompetitive modulation of substrate-induced serotonin release. Synapse. 2010 Nov;64(11):862-9. doi: 10.1002/syn.20804. [Article]
- Baumann MH, Bulling S, Benaderet TS, Saha K, Ayestas MA, Partilla JS, Ali SF, Stockner T, Rothman RB, Sandtner W, Sitte HH: Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates. Neuropsychopharmacology. 2014 May;39(6):1355-65. doi: 10.1038/npp.2013.331. Epub 2013 Nov 28. [Article]
- FDA Approved Drug Products: Fintepla (fenfluramine) oral solution [Link]
- PubChem: fenfluramine [Link]
- MSDS: fenfluramine [Link]
- External Links
- Human Metabolome Database
- HMDB0252200
- KEGG Drug
- D07945
- KEGG Compound
- C06996
- PubChem Compound
- 3337
- PubChem Substance
- 46506096
- ChemSpider
- 3220
- BindingDB
- 84738
- 4328
- ChEBI
- 5000
- ChEMBL
- CHEMBL87493
- Therapeutic Targets Database
- DAP001478
- PharmGKB
- PA449592
- RxList
- RxList Drug Page
- Wikipedia
- Fenfluramine
- MSDS
- Download (25.2 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Other Cognitive Functioning 1 4 Recruiting Treatment Epileptic Encephalopathy With Continuous Spike and Waves During Sleep (ECSWS) / Inv Dup(15) Encephalopathy / Multifocal or Bilateral Malformations of Cortical Development / Refractory Epilepsy / STXBP1 Encephalopathy With Epilepsy / SYNGAP1 Encephalopathy 1 3 Active Not Recruiting Treatment Dravet Syndrome (DS) / Epileptic Encephalopathy / Lennox-Gastaut Syndrome 1 3 Active Not Recruiting Treatment Lennox-Gastaut Syndrome 1 3 Active Not Recruiting Treatment Photosensitive Epilepsy 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Solution Oral 2.2 mg/1mL Solution Oral 2.2 MG/ML Tablet Oral Tablet Oral 20 mg / tab Tablet Oral 20 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9603815 Yes 2017-03-28 2033-11-03 US US9549909 Yes 2017-01-24 2033-11-03 US US10452815 Yes 2019-10-22 2038-12-29 US US9610260 Yes 2017-04-04 2033-11-03 US US9603814 Yes 2017-03-28 2033-11-03 US US10603290 Yes 2020-03-31 2038-02-02 US US10478442 Yes 2019-11-19 2033-11-03 US US10478441 Yes 2019-11-19 2033-11-03 US US10950331 Yes 2021-03-16 2036-03-28 US US10947183 Yes 2021-03-16 2037-06-20 US US11040018 Yes 2021-06-22 2038-02-02 US US11406606 Yes 2018-02-02 2038-02-02 US US11759440 Yes 2018-02-02 2038-02-02 US US11786487 Yes 2018-02-02 2038-02-02 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 160-170 L14632 boiling point (°C) 108-112 L14632 water solubility 412 mg/L L14632 pKa 9.92 L14632 - Predicted Properties
Property Value Source Water Solubility 0.0215 mg/mL ALOGPS logP 3.3 ALOGPS logP 3.47 Chemaxon logS -4 ALOGPS pKa (Strongest Basic) 10.22 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 1 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 12.03 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 59.2 m3·mol-1 Chemaxon Polarizability 22.69 Å3 Chemaxon Number of Rings 1 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule Yes Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.9868 Caco-2 permeable + 0.7004 P-glycoprotein substrate Non-substrate 0.5138 P-glycoprotein inhibitor I Non-inhibitor 0.5934 P-glycoprotein inhibitor II Non-inhibitor 0.8383 Renal organic cation transporter Non-inhibitor 0.7404 CYP450 2C9 substrate Non-substrate 0.8506 CYP450 2D6 substrate Substrate 0.8919 CYP450 3A4 substrate Non-substrate 0.6781 CYP450 1A2 substrate Inhibitor 0.8859 CYP450 2C9 inhibitor Non-inhibitor 0.8616 CYP450 2D6 inhibitor Inhibitor 0.7253 CYP450 2C19 inhibitor Non-inhibitor 0.5205 CYP450 3A4 inhibitor Non-inhibitor 0.5219 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6657 Ames test Non AMES toxic 0.8808 Carcinogenicity Non-carcinogens 0.6397 Biodegradation Not ready biodegradable 0.984 Rat acute toxicity 3.1255 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9666 hERG inhibition (predictor II) Inhibitor 0.7811
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 153.16994 predictedDeepCCS 1.0 (2019) [M+H]+ 155.52794 predictedDeepCCS 1.0 (2019) [M+Na]+ 162.65924 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- SubstrateInhibitor
- Curator comments
- Fenfluramine, as well as its active metabolite norfenfluramine, are substrates for the SERT transporter. Through an incompletely understood mechanism, potentially involving ion exchange, the transport of these compounds results in a reversal of SERT transport and an increase in extracellular 5-HT.
- General Function
- Serotonin:sodium symporter activity
- Specific Function
- Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into t...
- Gene Name
- SLC6A4
- Uniprot ID
- P31645
- Uniprot Name
- Sodium-dependent serotonin transporter
- Molecular Weight
- 70324.165 Da
References
- Rothman RB, Zolkowska D, Baumann MH: Serotonin (5-HT) transporter ligands affect plasma 5-HT in rats. Ann N Y Acad Sci. 2008 Oct;1139:268-84. doi: 10.1196/annals.1432.042. [Article]
- Xie T, Tong L, McLane MW, Hatzidimitriou G, Yuan J, McCann U, Ricaurte G: Loss of serotonin transporter protein after MDMA and other ring-substituted amphetamines. Neuropsychopharmacology. 2006 Dec;31(12):2639-51. Epub 2006 Jan 25. [Article]
- Johnson GJ, Leis LA, Dunlop PC, Weir EK: The effect of the anorectic agent, d-fenfluramine, and its primary metabolite, d-norfenfluramine, on intact human platelet serotonin uptake and efflux. J Thromb Haemost. 2003 Dec;1(12):2663-8. [Article]
- Rothman RB, Jayanthi S, Wang X, Dersch CM, Cadet JL, Prisinzano T, Rice KC, Baumann MH: High-dose fenfluramine administration decreases serotonin transporter binding, but not serotonin transporter protein levels, in rat forebrain. Synapse. 2003 Dec 1;50(3):233-9. [Article]
- Rothman RB, Baumann MH, Blough BE, Jacobson AE, Rice KC, Partilla JS: Evidence for noncompetitive modulation of substrate-induced serotonin release. Synapse. 2010 Nov;64(11):862-9. doi: 10.1002/syn.20804. [Article]
- Baumann MH, Bulling S, Benaderet TS, Saha K, Ayestas MA, Partilla JS, Ali SF, Stockner T, Rothman RB, Sandtner W, Sitte HH: Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates. Neuropsychopharmacology. 2014 May;39(6):1355-65. doi: 10.1038/npp.2013.331. Epub 2013 Nov 28. [Article]
- FDA Approved Drug Products: Fintepla (fenfluramine) oral solution [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Serotonin receptor activity
- Specific Function
- G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive subst...
- Gene Name
- HTR1D
- Uniprot ID
- P28221
- Uniprot Name
- 5-hydroxytryptamine receptor 1D
- Molecular Weight
- 41906.38 Da
References
- Schoonjans AS, Ceulemans B: An Old Drug for a New Indication: Repurposing Fenfluramine From an Anorexigen to an Antiepileptic Drug. Clin Pharmacol Ther. 2019 Nov;106(5):929-932. doi: 10.1002/cpt.1469. Epub 2019 May 22. [Article]
- Sourbron J, Schneider H, Kecskes A, Liu Y, Buening EM, Lagae L, Smolders I, de Witte P: Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model. ACS Chem Neurosci. 2016 May 18;7(5):588-98. doi: 10.1021/acschemneuro.5b00342. Epub 2016 Feb 17. [Article]
- Sourbron J, Smolders I, de Witte P, Lagae L: Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish. Front Pharmacol. 2017 Apr 6;8:191. doi: 10.3389/fphar.2017.00191. eCollection 2017. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Serotonin receptor activity
- Specific Function
- G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-...
- Gene Name
- HTR2C
- Uniprot ID
- P28335
- Uniprot Name
- 5-hydroxytryptamine receptor 2C
- Molecular Weight
- 51820.705 Da
References
- Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, Sun JH, Link JR, Abbaszade I, Hollis JM, Largent BL, Hartig PR, Hollis GF, Meunier PC, Robichaud AJ, Robertson DW: Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol. 2000 Jan;57(1):75-81. [Article]
- McCreary AC, Filip M, Cunningham KA: Discriminative stimulus properties of (+/-)-fenfluramine: the role of 5-HT2 receptor subtypes. Behav Neurosci. 2003 Apr;117(2):212-21. [Article]
- Schuhler S, Clark A, Joseph W, Patel A, Lehnen K, Stratford E, Horan TL, Fone KC, Ebling FJ: Involvement of 5-HT receptors in the regulation of food intake in Siberian hamsters. J Neuroendocrinol. 2005 May;17(5):276-85. [Article]
- Miller KJ: Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity. Mol Interv. 2005 Oct;5(5):282-91. [Article]
- Nonogaki K, Nozue K, Oka Y: Hyperphagia alters expression of hypothalamic 5-HT2C and 5-HT1B receptor genes and plasma des-acyl ghrelin levels in Ay mice. Endocrinology. 2006 Dec;147(12):5893-900. Epub 2006 Sep 14. [Article]
- Martin P, de Witte PAM, Maurice T, Gammaitoni A, Farfel G, Galer B: Fenfluramine acts as a positive modulator of sigma-1 receptors. Epilepsy Behav. 2020 Apr;105:106989. doi: 10.1016/j.yebeh.2020.106989. Epub 2020 Mar 10. [Article]
- Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ: Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol. 1999 Sep;128(1):13-20. [Article]
- Rodriguez-Munoz M, Sanchez-Blazquez P, Garzon J: Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget. 2018 May 4;9(34):23373-23389. doi: 10.18632/oncotarget.25169. eCollection 2018 May 4. [Article]
- Schoonjans AS, Ceulemans B: An Old Drug for a New Indication: Repurposing Fenfluramine From an Anorexigen to an Antiepileptic Drug. Clin Pharmacol Ther. 2019 Nov;106(5):929-932. doi: 10.1002/cpt.1469. Epub 2019 May 22. [Article]
- Sourbron J, Schneider H, Kecskes A, Liu Y, Buening EM, Lagae L, Smolders I, de Witte P: Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model. ACS Chem Neurosci. 2016 May 18;7(5):588-98. doi: 10.1021/acschemneuro.5b00342. Epub 2016 Feb 17. [Article]
- Sourbron J, Smolders I, de Witte P, Lagae L: Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish. Front Pharmacol. 2017 Apr 6;8:191. doi: 10.3389/fphar.2017.00191. eCollection 2017. [Article]
- FDA Approved Drug Products: Fintepla (fenfluramine) oral solution [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Opioid receptor activity
- Specific Function
- Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma m...
- Gene Name
- SIGMAR1
- Uniprot ID
- Q99720
- Uniprot Name
- Sigma non-opioid intracellular receptor 1
- Molecular Weight
- 25127.52 Da
References
- Martin P, de Witte PAM, Maurice T, Gammaitoni A, Farfel G, Galer B: Fenfluramine acts as a positive modulator of sigma-1 receptors. Epilepsy Behav. 2020 Apr;105:106989. doi: 10.1016/j.yebeh.2020.106989. Epub 2020 Mar 10. [Article]
- Rodriguez-Munoz M, Sanchez-Blazquez P, Garzon J: Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget. 2018 May 4;9(34):23373-23389. doi: 10.18632/oncotarget.25169. eCollection 2018 May 4. [Article]
- Schoonjans AS, Ceulemans B: An Old Drug for a New Indication: Repurposing Fenfluramine From an Anorexigen to an Antiepileptic Drug. Clin Pharmacol Ther. 2019 Nov;106(5):929-932. doi: 10.1002/cpt.1469. Epub 2019 May 22. [Article]
- Sourbron J, Smolders I, de Witte P, Lagae L: Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish. Front Pharmacol. 2017 Apr 6;8:191. doi: 10.3389/fphar.2017.00191. eCollection 2017. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Agonist
- Curator comments
- It is unclear whether or not 5-HT2A receptor agonism plays a role in reduction of epileptiform activity in Dravet syndrome.
- General Function
- Virus receptor activity
- Specific Function
- G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodop...
- Gene Name
- HTR2A
- Uniprot ID
- P28223
- Uniprot Name
- 5-hydroxytryptamine receptor 2A
- Molecular Weight
- 52602.58 Da
References
- Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, Sun JH, Link JR, Abbaszade I, Hollis JM, Largent BL, Hartig PR, Hollis GF, Meunier PC, Robichaud AJ, Robertson DW: Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol. 2000 Jan;57(1):75-81. [Article]
- Martin P, de Witte PAM, Maurice T, Gammaitoni A, Farfel G, Galer B: Fenfluramine acts as a positive modulator of sigma-1 receptors. Epilepsy Behav. 2020 Apr;105:106989. doi: 10.1016/j.yebeh.2020.106989. Epub 2020 Mar 10. [Article]
- Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ: Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol. 1999 Sep;128(1):13-20. [Article]
- Rodriguez-Munoz M, Sanchez-Blazquez P, Garzon J: Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget. 2018 May 4;9(34):23373-23389. doi: 10.18632/oncotarget.25169. eCollection 2018 May 4. [Article]
- Schoonjans AS, Ceulemans B: An Old Drug for a New Indication: Repurposing Fenfluramine From an Anorexigen to an Antiepileptic Drug. Clin Pharmacol Ther. 2019 Nov;106(5):929-932. doi: 10.1002/cpt.1469. Epub 2019 May 22. [Article]
- Sourbron J, Schneider H, Kecskes A, Liu Y, Buening EM, Lagae L, Smolders I, de Witte P: Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model. ACS Chem Neurosci. 2016 May 18;7(5):588-98. doi: 10.1021/acschemneuro.5b00342. Epub 2016 Feb 17. [Article]
- Sourbron J, Smolders I, de Witte P, Lagae L: Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish. Front Pharmacol. 2017 Apr 6;8:191. doi: 10.3389/fphar.2017.00191. eCollection 2017. [Article]
- FDA Approved Drug Products: Fintepla (fenfluramine) oral solution [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Agonist
- Curator comments
- Although fenfluramine does exhibit agonist activity at the 5-HT2B receptor, it has been demonstrated that this modulation has no activity in regards to improving seizure control in animal models of Dravet syndrome.
- General Function
- Serotonin receptor activity
- Specific Function
- G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various ergot alkaloid derivatives and psychoactive substances. Ligand binding causes a conformation...
- Gene Name
- HTR2B
- Uniprot ID
- P41595
- Uniprot Name
- 5-hydroxytryptamine receptor 2B
- Molecular Weight
- 54297.41 Da
References
- Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, Valentine PA, Sun JH, Link JR, Abbaszade I, Hollis JM, Largent BL, Hartig PR, Hollis GF, Meunier PC, Robichaud AJ, Robertson DW: Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol. 2000 Jan;57(1):75-81. [Article]
- Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL: Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000 Dec 5;102(23):2836-41. [Article]
- Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL: 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol Pharmacol. 2003 Jun;63(6):1223-9. [Article]
- Blanpain C, Le Poul E, Parma J, Knoop C, Detheux M, Parmentier M, Vassart G, Abramowicz MJ: Serotonin 5-HT(2B) receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension. Cardiovasc Res. 2003 Dec 1;60(3):518-28. [Article]
- Kaumann AJ, Levy FO: 5-hydroxytryptamine receptors in the human cardiovascular system. Pharmacol Ther. 2006 Sep;111(3):674-706. [Article]
- Roth BL: Drugs and valvular heart disease. N Engl J Med. 2007 Jan 4;356(1):6-9. [Article]
- Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC: Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome. Brain. 2017 Mar 1;140(3):669-683. doi: 10.1093/brain/aww342. [Article]
- Martin P, de Witte PAM, Maurice T, Gammaitoni A, Farfel G, Galer B: Fenfluramine acts as a positive modulator of sigma-1 receptors. Epilepsy Behav. 2020 Apr;105:106989. doi: 10.1016/j.yebeh.2020.106989. Epub 2020 Mar 10. [Article]
- Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ: Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol. 1999 Sep;128(1):13-20. [Article]
- Sourbron J, Schneider H, Kecskes A, Liu Y, Buening EM, Lagae L, Smolders I, de Witte P: Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model. ACS Chem Neurosci. 2016 May 18;7(5):588-98. doi: 10.1021/acschemneuro.5b00342. Epub 2016 Feb 17. [Article]
- Sourbron J, Smolders I, de Witte P, Lagae L: Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish. Front Pharmacol. 2017 Apr 6;8:191. doi: 10.3389/fphar.2017.00191. eCollection 2017. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Agonist
- Curator comments
- It is unlikely that fenfluramine exerts any significant effect through the 5-HT1A receptor.
- General Function
- Serotonin receptor activity
- Specific Function
- G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers...
- Gene Name
- HTR1A
- Uniprot ID
- P08908
- Uniprot Name
- 5-hydroxytryptamine receptor 1A
- Molecular Weight
- 46106.335 Da
References
- Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC: Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome. Brain. 2017 Mar 1;140(3):669-683. doi: 10.1093/brain/aww342. [Article]
- Martin P, de Witte PAM, Maurice T, Gammaitoni A, Farfel G, Galer B: Fenfluramine acts as a positive modulator of sigma-1 receptors. Epilepsy Behav. 2020 Apr;105:106989. doi: 10.1016/j.yebeh.2020.106989. Epub 2020 Mar 10. [Article]
- Rodriguez-Munoz M, Sanchez-Blazquez P, Garzon J: Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget. 2018 May 4;9(34):23373-23389. doi: 10.18632/oncotarget.25169. eCollection 2018 May 4. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58293.76 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55930.545 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Oxygen binding
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- Curator comments
- The extent to which fenfluramine inhibits CYP2D6 is unclear; it is unlikely to be relevant at clinically useful concentrations.
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- Haritos VS, Ching MS, Ghabrial H, Gross AS, Taavitsainen P, Pelkonen O, Battaglia SE, Smallwood RA, Ahokas JT: Metabolism of dexfenfluramine in human liver microsomes and by recombinant enzymes: role of CYP2D6 and 1A2. Pharmacogenetics. 1998 Oct;8(5):423-32. [Article]
- von Moltke LL, Greenblatt DJ, Ciraulo DA, Grassi JM, Granda BW, Duan SX, Harmatz JS, Shader RI: Appetite suppressant drugs as inhibitors of human cytochromes P450: in vitro inhibition of P450-2D6 by D- and L-fenfluramine, but not phentermine. J Clin Psychopharmacol. 1998 Aug;18(4):338-41. [Article]
- Flockhart Table of Drug Interactions [Link]
- FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
- FDA Approved Drug Products: Fintepla (fenfluramine) oral solution [Link]
Drug created at June 13, 2005 13:24 / Updated at December 02, 2023 06:52