Netupitant

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

Netupitant blood plasma levels are expected to increase when combined with inhibitors of the liver enzyme CYP3A4 and lowered when combined with inductors of this enzyme.

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, the anti-cancer drugs docetaxel and etoposide, and to a minor (not clinically significant) extent with levonorgestrel, erythromycin and midazolam. The clinical relevance of the anti-cancer drug interactions has been questioned.{{cite journal | vauthors = Natale JJ, Spinelli T, Calcagnile S, Lanzarotti C, Rossi G, Cox D, Kashef K | title = Drug-drug interaction profile of components of a fixed combination of netupitant and palonosetron: Review of clinical data | journal = Journal of Oncology Pharmacy Practice | volume = 22 | issue = 3 | pages = 485–495 | date = June 2016 | pmid = 25998320 | pmc = 4843089 | doi = 10.1177/1078155215586824 }}

Netupitant is a selective NK₁ receptor antagonist.{{cite journal | vauthors = Rizzi A, Campi B, Camarda V, Molinari S, Cantoreggi S, Regoli D, Pietra C, Calo' G | title = In vitro and in vivo pharmacological characterization of the novel NK₁ receptor selective antagonist Netupitant | journal = Peptides | volume = 37 | issue = 1 | pages = 86–97 | date = September 2012 | pmid = 22732666 | doi = 10.1016/j.peptides.2012.06.010 | s2cid = 7982557 }}

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.{{Cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/Netupitant#section=Top|title=Netupitant | work = PubChem | publisher = U.S. National Library of Medicine |access-date=2018-12-31|archive-date=2019-01-01|archive-url=https://web.archive.org/web/20190101051458/https://pubchem.ncbi.nlm.nih.gov/compound/Netupitant#section=Top|url-status=live}}

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 to more than 99%, and M2 protein binding is 97%.

The substance is mainly metabolized by CYP3A4, and to a lesser extent by CYP2D6 and CYP2C9. The main metabolites are desmethyl-netupitant (M1), netupitant N-oxide (M2), and hydroxy-netupitant (M3); all three are pharmacologically active.{{cite journal | vauthors = Spinelli T, Calcagnile S, Giuliano C, Rossi G, Lanzarotti C, Mair S, Stevens L, Nisbet I | title = Netupitant PET imaging and ADME studies in humans | journal = Journal of Clinical Pharmacology | volume = 54 | issue = 1 | pages = 97–108 | date = January 2014 | pmid = 24122871 | pmc = 4282341 | doi = 10.1002/jcph.198 }}

Netupitant and its metabolites are mainly excreted via the faeces. Biological half-life is 88 hours, significantly longer than that of the first NK₁ receptor antagonist, aprepitant, which has a half-life of 9 to 13 hours.{{cite book|title=Austria-Codex| veditors = Haberfeld H |publisher=Österreichischer Apothekerverlag |location=Vienna |year=2015 |language=de}}

File:Netupitant metabolites.svg

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• {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/netupitant | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Netupitant }}
• {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/netupitant%20%252F%20palonosetron | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Netupitant mixture with palonosetron }}

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Category:Antiemetics

Category:NK1 receptor antagonists

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Category:4-Methylpiperazin-1-yl compounds

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