Neurokinin-1 receptor
Fosaprepitant (1 mg/mL in 0.9 % sodium chloride injection solution) was combined in binary or tertiary fashion with therapeutic-dose preparations of a 5-HT3 antagonist (ondansetron, granisetron, palonosetron, or tropisetron) and/or a corticosteroid (dexamethasone sodium phosphate or methylprednisolone sodium succinate). For diluent compatibility assessment, fosaprepitant was also prepared 1 mg/mL in 0.9 % sodium chloride injection solution, water for injection, or 5 % dextrose injection solution. After 24-h storage under ambient conditions, samples were assayed for degradation[3].
Fosaprepitant is a neurokinin Type 1 receptor (NK1R) antagonist. It is a water-soluble prodrug of aprepitant. [1]

Fosaprepitant (1 mg/mL in 0.9 % sodium chloride injection solution) was combined in binary or tertiary fashion with therapeutic-dose preparations of a 5-HT3 antagonist (ondansetron, granisetron, palonosetron, or tropisetron) and/or a corticosteroid (dexamethasone sodium phosphate or methylprednisolone sodium succinate). For diluent compatibility assessment, fosaprepitant was also prepared 1 mg/mL in 0.9 % sodium chloride injection solution, water for injection, or 5 % dextrose injection solution. After 24-h storage under ambient conditions, samples were assayed for degradation[3].

Fosaprepitant (30 mg/kg; i.p.; daily; for 7 days) reduces morphine tolerance and heightens the antinociceptive impact in rats[1].

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In Sprague-Dawley rats, subcutaneous administration of morphine (10 mg/kg, twice daily) alone produced a significant antinociceptive effect on day 1, which decreased by day 4, indicating the development of tolerance. [1]
Intraperitoneal administration of fosaprepitant (30 mg/kg, once daily) alone did not produce any significant antinociceptive effect compared to the control (saline) group. [1]
Co-administration of fosaprepitant (30 mg/kg, i.p., 30 minutes before morphine) with morphine (10 mg/kg, s.c., twice daily) for 7 days significantly attenuated the development of morphine tolerance. The combination group showed a higher antinociceptive effect (measured as % Maximum Possible Effect, %MPE, in the hot plate test) compared to the morphine-alone group on days 1 (P < 0.01) and 3 (P < 0.001), and compared to the control group from days 1 to 4 (P < 0.001). [1]
Immunohistochemical analysis of the spinal cord (cervical enlargement) showed that the expression of Substance P (SP) was significantly increased in the superficial laminae (I-II) of the dorsal horn in the morphine + fosaprepitant co-treatment group compared to all other groups (P < 0.001). The expression of Calcitonin Gene-Related Peptide (CGRP) was not significantly altered by any treatment. [1]

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In Sprague-Dawley rats, subcutaneous administration of morphine (10 mg/kg, twice daily) alone produced a significant antinociceptive effect on day 1, which decreased by day 4, indicating the development of tolerance. [1]
Intraperitoneal administration of fosaprepitant (30 mg/kg, once daily) alone did not produce any significant antinociceptive effect compared to the control (saline) group. [1]
Co-administration of fosaprepitant (30 mg/kg, i.p., 30 minutes before morphine) with morphine (10 mg/kg, s.c., twice daily) for 7 days significantly attenuated the development of morphine tolerance. The combination group showed a higher antinociceptive effect (measured as % Maximum Possible Effect, %MPE, in the hot plate test) compared to the morphine-alone group on days 1 (P < 0.01) and 3 (P < 0.001), and compared to the control group from days 1 to 4 (P < 0.001). [1]
Immunohistochemical analysis of the spinal cord (cervical enlargement) showed that the expression of Substance P (SP) was significantly increased in the superficial laminae (I-II) of the dorsal horn in the morphine + fosaprepitant co-treatment group compared to all other groups (P < 0.001). The expression of Calcitonin Gene-Related Peptide (CGRP) was not significantly altered by any treatment. [1]

Sprague-Dawley rats
30 mg/kg
Intraperitoneal injection, daily, for 7 days

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Sprague-Dawley rats were injected with morphine (10 mg/kg twice daily) and/or fosaprepitant (30 mg/kg once daily) for 7 days. Pain threshold was assessed by the hot plate test. Expression of SP and calcitonin gene-related peptide (CGRP) in the spinal cords of these rats was evaluated by immunohistochemistry.[2]

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Fosaprepitant (also known as MK-0517 and L-758,298) is a water-soluble phosphoryl prodrug for aprepitant, which, when administered intravenously, is converted to aprepitant within 30 min of intravenous administration via the action of ubiquitous phosphatases. Owing to the rapid conversion of fosaprepitant to the active form (aprepitant), fosaprepitant 115 mg provided the same aprepitant exposure in terms of AUC as aprepitant 12 mg orally, and fosaprepitant is expected to provide a correspondingly similar antiemetic effect as aprepitant. Clinical studies have suggested that fosaprepitant could be appropriate as an intravenous alternative to the aprepitant oral capsule. In a study in healthy subjects, fosaprepitant 115 mg was generally well tolerated at a final drug concentration of 1 mg/ml, and fosaprepitant 115 mg was AUC bioequivalent to aprepitant 125 mg. Fosaprepitant in the dose of 115 mg has been approved by the US FDA, the EU and the Australian authorities on day 1 of a 3-day oral aprepitant regimen, with oral aprepitant administered on days 2 and 3. Fosaprepitant may be a useful parenteral alternative to oral aprepitant. Further study is needed to clarify the utility of fosaprepitant in the prevention of CINV and to clarify optimal dosing regimens that may be appropriate substitutes for oral aprepitant[2].

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Animals: Male Sprague-Dawley rats (n=24, ~250 g) were used. [1]
Grouping and Dosing: Rats were divided into four groups (n=6 each). Group I (Control): received physiological saline subcutaneously (s.c.), twice daily. Group II (Morphine): received morphine sulfate (10 mg/kg, s.c.), twice daily. Group III (Fosaprepitant): received fosaprepitant (30 mg/kg, intraperitoneally, i.p.), once daily. Group IV (Combination): received both fosaprepitant (30 mg/kg, i.p., once daily) and morphine (10 mg/kg, s.c., twice daily). In the combination group, fosaprepitant was injected 30 minutes before each morphine injection. The treatment continued for 7 days. [1]
Pain Assessment (Hot Plate Test): The antinociceptive effect was assessed using a hot plate apparatus set at 52.5°C. Testing was performed in the morning, 40 minutes after saline, fosaprepitant, or morphine injection (corresponding to the peak effect time for morphine). The latency period (in seconds) to a behavioral endpoint (licking hind paw or jumping) was recorded, with a 40-second cut-off to prevent tissue damage. The test was repeated three times at 5-7 minute intervals, and the average latency was used. Testing was done at 24-hour intervals. The data were normalized and expressed as Percent Maximum Possible Effect (%MPE). [1]
Tissue Collection and Analysis: On day 8, rats were anesthetized and perfused. The cervical spinal cord was removed. Transverse sections (20 µm) were cut and processed for immunohistochemistry to detect Substance P (SP) and Calcitonin Gene-Related Peptide (CGRP) expression in the superficial dorsal horn laminae (I-II). Image analysis was performed to quantify immunoreactivity. [1]

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Animals: Male Sprague-Dawley rats (n=24, ~250 g) were used. [1]
Grouping and Dosing: Rats were divided into four groups (n=6 each). Group I (Control): received physiological saline subcutaneously (s.c.), twice daily. Group II (Morphine): received morphine sulfate (10 mg/kg, s.c.), twice daily. Group III (Fosaprepitant): received fosaprepitant (30 mg/kg, intraperitoneally, i.p.), once daily. Group IV (Combination): received both fosaprepitant (30 mg/kg, i.p., once daily) and morphine (10 mg/kg, s.c., twice daily). In the combination group, fosaprepitant was injected 30 minutes before each morphine injection. The treatment continued for 7 days. [1]
Pain Assessment (Hot Plate Test): The antinociceptive effect was assessed using a hot plate apparatus set at 52.5°C. Testing was performed in the morning, 40 minutes after saline, fosaprepitant, or morphine injection (corresponding to the peak effect time for morphine). The latency period (in seconds) to a behavioral endpoint (licking hind paw or jumping) was recorded, with a 40-second cut-off to prevent tissue damage. The test was repeated three times at 5-7 minute intervals, and the average latency was used. Testing was done at 24-hour intervals. The data were normalized and expressed as Percent Maximum Possible Effect (%MPE). [1]
Tissue Collection and Analysis: On day 8, rats were anesthetized and perfused. The cervical spinal cord was removed. Transverse sections (20 µm) were cut and processed for immunohistochemistry to detect Substance P (SP) and Calcitonin Gene-Related Peptide (CGRP) expression in the superficial dorsal horn laminae (I-II). Image analysis was performed to quantify immunoreactivity. [1]

Absorption, Distribution and Excretion
Aprepitant is primarily eliminated through metabolism; it is not excreted by the kidneys. Aprepitant is secreted into rat milk. It is unknown whether this drug is secreted into human milk. Metabolism/Metabolites Aprepitant is primarily metabolized by CYP3A4, with minor metabolism by CYP1A2 and CYP2C19. Seven less active aprepitant metabolites have been identified in human plasma. Biological Half-Life 9–13 hours Fosapirant is a water-soluble phosphorus amide prodrug of aprepitant. After intravenous administration, it is rapidly converted to aprepitant, with a half-life of approximately 30 minutes in rats. [1]
This prodrug design allows for a high and sustained occupancy of the NK1 receptor in the central nervous system (CNS) (a human PET imaging study cited by the authors reported a receptor occupancy of 41-75% 120 hours after administration). [1]
Notably, there is a potential pharmacokinetic interaction: aprepitant (the active metabolite) is metabolized by CYP3A4. Morphine undergoes N-demethylation via CYP3A4 in rodents. Concomitant administration may increase the concentration of morphine in the nervous system, leading to the observed enhancement effect. [1]
Fosapitant is a water-soluble phosphoramide ester prodrug of aprepitant. After intravenous injection, it is rapidly converted to aprepitant, with a half-life of approximately 30 minutes in rats. [1]
This prodrug design allows for a high and sustained occupancy of the NK1 receptor in the central nervous system (CNS) (a human PET imaging study cited by the authors reported a receptor occupancy of 41-75% 120 hours after administration). [1]
Notably, there is a potential pharmacokinetic interaction: aprepitant (the active metabolite) is metabolized by CYP3A4. Morphine undergoes N-demethylation via CYP3A4 in rodents. Concomitant administration may increase the concentration of morphine in the nervous system, leading to the observed enhancement effect. [1]

Protein Binding
95%+

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It has been reported that the approximate LD₅₀ of fosaprepitant in rats is >200 mg/kg. [1]

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It has been reported that the approximate LD₅₀ of fosaprepitant in rats is >200 mg/kg. [1]

[1]. Role of fosaprepitant, a neurokinin Type 1 receptor antagonist, in morphine-induced antinociception in rats. Indian J Pharmacol. 2016 Jul-Aug; 48(4): 394-398.

[2]. Fosaprepitant: a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Expert Rev Anticancer Ther . 2008 Nov;8(11):1733-42.
[3]. Compatibility of intravenous fosaprepitant with intravenous 5-HT3 antagonists and corticosteroids. Cancer Chemother Pharmacol . 2013 Sep;72(3):509-13.

Fosaprepitant is a morpholine derivative, the (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl ether of (3-{[(2R,3S)-3-(4-fluorophenyl)-2-hydroxymorpholin-4-yl]methyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phosphonic acid. It has the effects of an antiemetic, a neurokinin-1 receptor antagonist, and a prodrug. It belongs to the morpholine, triazole, cyclic acetal, phosphoramide, and (trifluoromethyl)benzene classes. It is the conjugate acid of Fosaprepitant (2-). Fosaprepitant is an intravenously administered antiemetic. It is a prodrug of aprepitan. It helps prevent acute and delayed nausea and vomiting induced by chemotherapy. Fosaprepitant is a substance P/neurokine-1 receptor antagonist. The mechanism of action of Fosaprepitant is as a neurokinin-1 receptor antagonist. Fosaspirantam dimethylglucamine is the dimethylglucamine salt form of fosaspirant, a water-soluble N-phosphorylated prodrug of aprepitant, and possesses antiemetic activity. Upon intravenous injection, this drug is rapidly converted to aprepitant, which selectively binds to human substance P/neurokine 1 (NK1) receptors in the central nervous system (CNS). Fosaspirantam is a water-soluble N-phosphorylated prodrug, a prodrug of aprepitant, a substance P (SP; neurokinin 1 (NK1)) antagonist, and possesses antiemetic activity. Upon intravenous injection, fosaspirantam is rapidly converted to aprepitant, which selectively binds to and blocks the action of human substance P receptors in the central nervous system (CNS). This inhibits the binding of endogenous substance P to its receptors, thereby preventing substance P-induced vomiting. See also: aprepitant (with the active fraction); fosaspirant dimethylglucamine (its active component).

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Drug Indications
Fosaprepitant is indicated for use in combination with other antiemetics in adult and pediatric patients aged 6 months and older to prevent acute and delayed nausea and vomiting induced by highly emetogenic chemotherapy for cancer (including high-dose cisplatin) during first and repeated cycles. It is also indicated for the treatment of delayed nausea and vomiting induced by moderately emetogenic chemotherapy for cancer during first and repeated cycles.
Prevention of nausea and vomiting induced by highly emetogenic and moderately emetogenic chemotherapy for cancer in adult and pediatric patients aged 6 months and older. Eviment 150 mg is administered as part of combination therapy.
Prevention of nausea and vomiting

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Mechanism of Action
Animal model studies have shown that aprepitan can inhibit vomiting induced by cytotoxic chemotherapy drugs such as cisplatin through central action. Animal and human positron emission tomography (PET) studies have shown that aprepitan can cross the blood-brain barrier and occupy NK1 receptors in the brain. Animal and human studies have shown that aprepitant enhances the antiemetic activity of the 5-HT3 receptor antagonist ondansetron and the corticosteroid ethasone, and inhibits both the acute and delayed phases of cisplatin-induced vomiting. In summary, the active form of fosaprepitant is an NK1 receptor antagonist because it blocks the signaling emitted by the NK1 receptor. Therefore, this reduces the likelihood of vomiting in patients.

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Pharmacodynamics
Fosaprepitant is the prodrug of aprepitant. After bioactivation, this drug acts as a substance P/neurokine 1 (NK1) receptor antagonist and, when used in combination with other antiemetics, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeated courses of highly emetogenic chemotherapy for cancers. Aprepitant is a selective high-affinity antagonist of the human substance P/neurokine 1 (NK1) receptor. Aprepitant has little affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, which are targets of existing chemotherapy-induced nausea and vomiting (CINV) therapies. Fosaprepitant (meglumine salt) is used clinically to prevent chemotherapy-induced nausea and vomiting (CINV). [1] This study explored its potential use as an adjunct to opioid analgesia. Its mechanism of action against morphine tolerance is thought to be antagonism of spinal NK1 receptors, which are activated by substance P (SP), a key neuropeptide in pain transmission and central sensitization. [1] The increased spinal SP immunoreactivity observed in the combination therapy group was interpreted as a potential consequence of NK1 receptor blockade leading to reduced presynaptic SP release and subsequent SP accumulation. [1] The interaction between morphine and fosaprepitant is thought to be synergistic, as fosaprepitant alone has no analgesic effect. [1] Fosaprepitant (meglumine salt) is used clinically to prevent chemotherapy-induced nausea and vomiting (CINV). [1] This study explores its potential as an adjunct to opioid analgesia. Its mechanism of action against morphine tolerance is thought to be antagonism of spinal NK1 receptors, which are activated by substance P (SP), a key neuropeptide in pain transmission and central sensitization. [1] The increased SP immunoreactivity in the spinal cord in the combination therapy group is interpreted as a potential consequence of NK1 receptor blockade leading to reduced SP release from presynaptic terminals, resulting in SP accumulation. [1] The interaction between morphine and fosaprepitant is considered synergistic, as fosaprepitant alone has no analgesic effect. [1]

C23H22F7N4O6P

614.41

614.116

C, 44.96; H, 3.61; F, 21.64; N, 9.12; O, 15.62; P, 5.04

172673-20-0

Fosaprepitant dimeglumine; 265121-04-8

135413538

Solid powder

1.7±0.1 g/cm3

588.9ºC at 760 mmHg

310ºC

1.03E-14mmHg at 25°C

1.590

2.14

3

15

7

41

997

3

O=C1N=C(CN2[C@@H](C3=CC=C(F)C=C3)[C@@H](O[C@H](C)C4=CC(C(F)(F)F)=CC(C(F)(F)F)=C4)OCC2)NN1P(O)(O)=O

BARDROPHSZEBKC-OITMNORJSA-N

InChI=1S/C23H22F7N4O6P/c1-12(14-8-15(22(25,26)27)10-16(9-14)23(28,29)30)40-20-19(13-2-4-17(24)5-3-13)33(6-7-39-20)11-18-31-21(35)34(32-18)41(36,37)38/h2-5,8-10,12,19-20H,6-7,11H2,1H3,(H,31,32,35)(H2,36,37,38)/t12-,19+,20-/m1/s1

[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl]-5-oxo-4H-1,2,4-triazol-1-yl]phosphonic acid

L-758298; L 758298; L758298; MK0517; MK 0517; Ivemend; fosaprepitantum; UNII-6L8OF9XRDC; 6L8OF9XRDC; L 758298; L-758298; MK-0517

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)