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). Recent mechanistic studies using NG108-15 cells have shown that palonosetron and netupitant, an NK1 receptor antagonist currently in phase 3 clinical trials, exhibited synergistic effects when inhibiting the substance P response.The present studies showed that both netupitant and palonosetron-induced NK1 receptor internalization in NG108-15 cells and that when used together receptor internalization was additive.Netupitant was well tolerated with most treatment emergent adverse events (AEs) being mild.Palonosetron and netupitant, either alone or in combination, were effective in reducing the induced elevated pPKA levels during the delayed phase.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO >9 mg/mL|
Differential and additive suppressive effects of 5-HT3 (palonosetron)- and NK1 (netupitant)-receptor antagonists on cisplatin-induced vomiting and ERK1/2, PKA and PKC activation.
Darmani NA, et al. Pharmacol Biochem Behav. 2015 Feb 14;131C:104-111. PMID: 25687374.
Netupitant and palonosetron trigger NK1 receptor internalization in NG108-15 cells.
Thomas AG, et al. Exp Brain Res. 2014 Aug;232(8):2637-44. PMID: 24969614.
Efficacy and safety of repeated dosing of netupitant, a neurokinin-1 receptor antagonist, in treating overactive bladder.
Haab F, et al. Neurourol Urodyn. 2014 Mar;33(3):335-40. PMID: 23765630.
|Related Neurokinin Receptor Products|
Substance P is a neuropeptide, acting as a neurotransmitter and as a neuromodulator.The endogenous receptor for substance P is neurokinin 1 receptor (NK1-receptor, NK1R).
SCH-619734 is an orally bioavailable, centrally-acting, selective neurokinin 1 receptor (NK1-receptor) antagonist with a Ki of 0.66 nM.
JNJ-31020028 is a selective brain penetrant antagonist of neuropeptide Y2 receptor with high affinity(pIC50=8.07, human; pIC50=8.22 rat); >100-fold selective versus human Y1/Y4/Y5 receptors.
Maropitant (Cerenia) is a novel, selective neurokinin type-1 (NK1) receptor antagonist.
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