# Netupitant

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Chemical compound

Pharmaceutical compound

Netupitant Clinical data License data EU EMA: by INN Drug class NK1 receptor antagonists, antiemetics ATC code None Pharmacokinetic data Bioavailability >60% (estimated) Protein binding >99% Metabolism mainly CYP3A4; also CYP2D6 and CYP2C9 Elimination half-life 88 hours Excretion 71% (faeces) Identifiers IUPAC name 2-[3,5-Bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]propanamide CAS Number 290297-26-6 PubChem CID 6451149 DrugBank DB09048 ChemSpider 4953629 UNII 7732P08TIR KEGG D05152 ChEBI CHEBI:85155 ChEMBL ChEMBL206253 CompTox Dashboard (EPA) DTXSID50183271 Chemical and physical data Formula C30H32F6N4O Molar mass 578.603 g·mol−1 3D model (JSmol) Interactive image SMILES Cc1ccccc1c2cc(ncc2N(C)C(=O)C(C)(C)c3cc(cc(c3)C(F)(F)F)C(F)(F)F)N4CCN(CC4)C InChI InChI=1S/C30H32F6N4O/c1-19-8-6-7-9-23(19)24-17-26(40-12-10-38(4)11-13-40)37-18-25(24)39(5)27(41)28(2,3)20-14-21(29(31,32)33)16-22(15-20)30(34,35)36/h6-9,14-18H,10-13H2,1-5H3 Key:WAXQNWCZJDTGBU-UHFFFAOYSA-N

**Netupitant** is an [antiemetic](/source/Antiemetic) medication. In the United States, the [combinations](/source/Combination_drug) of [netupitant/palonosetron](/source/Netupitant%2Fpalonosetron) and the prodrug [fosnetupitant](/source/Fosnetupitant)/[palonosetron](/source/Palonosetron) (both brand name **Akynzeo**) are approved by the [Food and Drug Administration](/source/Food_and_Drug_Administration) for the prevention of acute and delayed [chemotherapy-induced nausea and vomiting](/source/Chemotherapy-induced_nausea_and_vomiting), including highly [emetogenic](/source/Emetogenic) chemotherapy such as with [cisplatin](/source/Cisplatin).[1][2] In the European Union, the combinations are approved by the [European Medicines Agency](/source/European_Medicines_Agency) (EMA) for the same indication.[3][4]

## Adverse effects

Side effects of the combination netupitant/palonosetron are similar to palonosetron alone, so that no common side effects can be attributed to netupitant.[3][1]

## Interactions

Netupitant blood plasma levels are expected to increase when combined with inhibitors of the liver enzyme [CYP3A4](/source/CYP3A4) and lowered when combined with inductors of this enzyme.[3]

Being a CYP3A4 inhibitor itself, netupitant could also increase plasma levels of pharmaceuticals that are metabolized by CYP3A4. This effect has been observed with [dexamethasone](/source/Dexamethasone), the anti-cancer drugs [docetaxel](/source/Docetaxel) and [etoposide](/source/Etoposide), and to a minor (not clinically significant) extent with [levonorgestrel](/source/Levonorgestrel), [erythromycin](/source/Erythromycin) and [midazolam](/source/Midazolam).[3] The clinical relevance of the anti-cancer drug interactions has been questioned.[5]

## Pharmacology

### Mechanism of action

Netupitant is a selective [NK1 receptor antagonist](/source/NK1_receptor_antagonist).[6]

Netupitant is a selective neurokinin 1 (NK1) receptor antagonist with potential antiemetic activity. Netupitant competitively binds to and blocks the activity of the human substance P/NK1 receptors in the central nervous system (CNS), thereby inhibiting NK1-receptor binding of the endogenous tachykinin neuropeptide substance P (SP), which may result in the prevention of chemotherapy-induced nausea and vomiting (CINV). SP is found in neurons of vagal afferent fibers innervating the brain-stem nucleus tractus solitarii and the area postrema, which contains the chemoreceptor trigger zone (CTZ), and may be elevated in response to chemotherapy. The NK-receptor is a G-protein receptor coupled to the inositol phosphate signal-transduction pathway and is found in both the nucleus tractus solitarii and the area postrema.[7]

### Pharmacokinetics

[Bioavailability](/source/Bioavailability) is estimated to be over 60% for orally taken netupitant. Highest blood plasma concentrations are reached five hours after application. Availability is moderately (10–20%) increased when taken after a fatty meal. Netupitant and its main metabolites (called M1 and M3) are bound to [plasma proteins](/source/Plasma_proteins) to more than 99%, and M2 protein binding is 97%.[3]

The substance is mainly metabolized by CYP3A4, and to a lesser extent by [CYP2D6](/source/CYP2D6) and [CYP2C9](/source/CYP2C9). The main metabolites are [desmethyl](/source/Desmethyl)-netupitant (M1), netupitant [*N*-oxide](/source/Amine_oxide) (M2), and [hydroxy](/source/Hydroxyl)-netupitant (M3); all three are pharmacologically active.[3][8]

Netupitant and its metabolites are mainly excreted via the [faeces](/source/Faeces).[3] [Biological half-life](/source/Biological_half-life) is 88 hours, significantly longer than that of the first NK1 receptor antagonist, [aprepitant](/source/Aprepitant), which has a half-life of 9 to 13 hours.[9]

Netupitant metabolites[8]

## References

1. ^ [***a***](#cite_ref-Akynzeo_FDA_label_1-0) [***b***](#cite_ref-Akynzeo_FDA_label_1-1) ["Akynzeo- netupitant and palonosetron capsule Akynzeo- fosnetupitant and palonosetron injection"](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8e47618e-af46-4d82-94e8-1507c042252d). *DailyMed*. U.S. National Library of Medicine. 30 April 2018. [Archived](https://web.archive.org/web/20201018154534/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8e47618e-af46-4d82-94e8-1507c042252d) from the original on 18 October 2020. Retrieved 19 March 2020.

1. **[^](#cite_ref-2)** ["FDA approves Akynzeo for nausea and vomiting associated with cancer chemotherapy"](https://web.archive.org/web/20170201191145/http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm418375.htm) (Press release). [Food and Drug Administration](/source/Food_and_Drug_Administration). October 10, 2014. Archived from [the original](https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm418375.htm) on February 1, 2017. Retrieved December 16, 2019.

1. ^ [***a***](#cite_ref-EPAR_3-0) [***b***](#cite_ref-EPAR_3-1) [***c***](#cite_ref-EPAR_3-2) [***d***](#cite_ref-EPAR_3-3) [***e***](#cite_ref-EPAR_3-4) [***f***](#cite_ref-EPAR_3-5) [***g***](#cite_ref-EPAR_3-6) ["Akynzeo: Summary of Product Characteristics"](http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003728/WC500188432.pdf) (PDF). [European Medicines Agency](/source/European_Medicines_Agency). [Archived](https://web.archive.org/web/20160626122835/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003728/WC500188432.pdf) (PDF) from the original on 26 June 2016. Retrieved 12 July 2016.

1. **[^](#cite_ref-Akynzeo_EPAR_4-0)** ["Akynzeo EPAR"](https://www.ema.europa.eu/en/medicines/human/EPAR/akynzeo). *[European Medicines Agency](/source/European_Medicines_Agency) (EMA)*. 19 March 2020. [Archived](https://web.archive.org/web/20200319201955/https://www.ema.europa.eu/en/medicines/human/EPAR/akynzeo) from the original on 19 March 2020. Retrieved 19 March 2020.

1. **[^](#cite_ref-5)** Natale JJ, Spinelli T, Calcagnile S, Lanzarotti C, Rossi G, Cox D, et al. (June 2016). ["Drug-drug interaction profile of components of a fixed combination of netupitant and palonosetron: Review of clinical data"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843089). *Journal of Oncology Pharmacy Practice*. **22** (3): 485–495. [doi](/source/Doi_(identifier)):[10.1177/1078155215586824](https://doi.org/10.1177%2F1078155215586824). [PMC](/source/PMC_(identifier)) [4843089](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843089). [PMID](/source/PMID_(identifier)) [25998320](https://pubmed.ncbi.nlm.nih.gov/25998320).

1. **[^](#cite_ref-6)** Rizzi A, Campi B, Camarda V, Molinari S, Cantoreggi S, Regoli D, et al. (September 2012). "In vitro and in vivo pharmacological characterization of the novel NK₁ receptor selective antagonist Netupitant". *Peptides*. **37** (1): 86–97. [doi](/source/Doi_(identifier)):[10.1016/j.peptides.2012.06.010](https://doi.org/10.1016%2Fj.peptides.2012.06.010). [PMID](/source/PMID_(identifier)) [22732666](https://pubmed.ncbi.nlm.nih.gov/22732666). [S2CID](/source/S2CID_(identifier)) [7982557](https://api.semanticscholar.org/CorpusID:7982557).

1. **[^](#cite_ref-7)** ["Netupitant"](https://pubchem.ncbi.nlm.nih.gov/compound/Netupitant#section=Top). *PubChem*. U.S. National Library of Medicine. [Archived](https://web.archive.org/web/20190101051458/https://pubchem.ncbi.nlm.nih.gov/compound/Netupitant#section=Top) from the original on 2019-01-01. Retrieved 2018-12-31.

1. ^ [***a***](#cite_ref-Spinelli_8-0) [***b***](#cite_ref-Spinelli_8-1) Spinelli T, Calcagnile S, Giuliano C, Rossi G, Lanzarotti C, Mair S, et al. (January 2014). ["Netupitant PET imaging and ADME studies in humans"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282341). *Journal of Clinical Pharmacology*. **54** (1): 97–108. [doi](/source/Doi_(identifier)):[10.1002/jcph.198](https://doi.org/10.1002%2Fjcph.198). [PMC](/source/PMC_(identifier)) [4282341](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282341). [PMID](/source/PMID_(identifier)) [24122871](https://pubmed.ncbi.nlm.nih.gov/24122871).

1. **[^](#cite_ref-AC_9-0)** Haberfeld H, ed. (2015). *Austria-Codex* (in German). Vienna: Österreichischer Apothekerverlag.

## External links

- ["Netupitant"](https://web.archive.org/web/20200319202957/https://druginfo.nlm.nih.gov/drugportal/name/netupitant). *Drug Information Portal*. U.S. National Library of Medicine. Archived from [the original](https://druginfo.nlm.nih.gov/drugportal/name/netupitant) on March 19, 2020.

- ["Netupitant mixture with palonosetron"](https://web.archive.org/web/20191219060724/https://druginfo.nlm.nih.gov/drugportal/name/netupitant%2520%25252F%2520palonosetron). *Drug Information Portal*. U.S. National Library of Medicine. Archived from [the original](https://druginfo.nlm.nih.gov/drugportal/name/netupitant%20%252F%20palonosetron) on December 19, 2019.

v t e Antiemetics (A04) 5-HT3 serotonin ion channel antagonists Alosetron Azasetron Bemesetron Cilansetron Clozapine Dazopride Dolasetron Granisetron Lerisetron Mianserin Mirtazapine Olanzapine Ondansetron Palonosetron (+netupitant) Quetiapine Ramosetron Ricasetron Tropisetron Zatosetron 5-HT serotonin G-protein receptor antagonists Clozapine Cyproheptadine Hydroxyzine Olanzapine Risperidone Ziprasidone CB1 agonists (cannabinoids) Dronabinol Nabilone Tetrahydrocannabinol (cannabis) D2/D3 antagonists Chlorpromazine Haloperidol Hydroxyzine Metoclopramide Metopimazine Prochlorperazine Thiethylperazine Trimethobenzamide H1 antagonists (antihistamines) Cyclizine Dimenhydrinate Diphenhydramine Hydroxyzine Meclizine Promethazine mACh antagonists (anticholinergics) Atropine Diphenhydramine Hydroxyzine (very mild) Hyoscyamine Scopolamine NK1 antagonists Aprepitant Fosaprepitant Maropitant Netupitant Rolapitant Tradipitant Others Amisulpride Cerium oxalate Dexamethasone Lorazepam Midazolam Propofol

v t e Neurokinin receptor modulators NK1 Agonists: Substance P Antagonists: Aprepitant Befetupitant Burapitant Casopitant CI-1021 CP-96345 CP-99994 CP-122721 Dapitant Elinzanetant Ezlopitant Figopitant FK-888 Fosaprepitant Fosnetupitant GR-203040 GW-597599 HSP-117 L-733,060 L-741,671 L-743,310 L-758,298 Lanepitant LY-306740 Maropitant Netupitant NKP-608 Nolpitantium besilate Orvepitant Rolapitant RP-67580 SDZ NKT 343 Serlopitant T-2328 Telmapitant Tradipitant Vestipitant Vofopitant NK2 Agonists: Neurokinin A Antagonists: GR-159897 Ibodutant Nepadutant Saredutant Otilonium bromide NK3 Agonists: Neurokinin B Senktide Antagonists: Elinzanetant Fezolinetant Osanetant Pavinetant SB-218,795 SB-222,200 Talnetant

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Adapted from the Wikipedia article [Netupitant](https://en.wikipedia.org/wiki/Netupitant) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Netupitant?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.