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QuickView for Fosaprepitant (compound)

Summary
General Info

PubChem

PubChem Compound 11214788

Name:	aprepitant
PubChem Compound ID:	11214788
Molecular formula:	C₂₃H₂₁F₇N₄O₃
Molecular weight:	536.419 g/mol

DrugBank

Identification

Name:	aprepitant
Name (isomeric):	DB00673
Drug Type:	small molecule
Synonyms:	MK-0517; MK-869
Brand:	Emend
Category:	Antiemetics
CAS number:	170729-80-3

Pharmacology

Indication:	For the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including high-dose cisplatin (in combination with other antiemetic agents).
Pharmacology:	Aprepitant, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of hum... show more » Aprepitant, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT₃), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV). show less «
Mechanism of Action:	Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepit... show more » Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepitant augments 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 emesis. show less «
Absorption:	The mean absolute oral bioavailability of aprepitant is approximately 60 to 65%.
Protein binding:	>95%
Biotransformation:	Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.
Route of elimination:	Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk.
Half Life:	9-13 hours
Clearance:	Apparent plasma cl=62-90 mL/min
Affected organisms:	Humans and other mammals

Interactions

Food interaction:

Take without regard to meals.

Drug interaction:

Tamsulosin	Aprepitant, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Aprepitant is initiated, discontinued, or dose changed.
Nefazodone	This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Itraconazole	This CYP3A4 inhibitor, itraconazole, may increase the effect and toxicity of aprepitant.
Midazolam	Aprepitant may increase the effect and toxicity of the benzodiazepine, midazolam.
Clarithromycin	The CYP3A4 inhibitor, clarithromycin, may increase the effect and toxicity of aprepitant.

Tamsulosin	Aprepitant, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Aprepitant is initiated, discontinued, or dose changed.
Nefazodone	This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Itraconazole	This CYP3A4 inhibitor, itraconazole, may increase the effect and toxicity of aprepitant.
Midazolam	Aprepitant may increase the effect and toxicity of the benzodiazepine, midazolam.
Clarithromycin	The CYP3A4 inhibitor, clarithromycin, may increase the effect and toxicity of aprepitant.
Vinorelbine	Aprepitant may change levels of the chemotherapy agent, vinorelbine.
Anisindione	Aprepitant may decrease the anticoagulant effect of anisindione by decreasing its serum concentration.
Tolterodine	Aprepitant may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.
Dicumarol	Aprepitant may decrease the anticoagulant effect of dicumarol by decreasing its serum concentration.
Troleandomycin	This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Phenytoin	The CYP3A4 inducer, phenytoin, may decrease the effect of aprepitant.
Etoposide	Aprepitant may change levels of the chemotherapy agent, etoposide.
Docetaxel	Aprepitant may change levels of the chemotherapy agent, docetaxel.
Trazodone	The CYP3A4 inhibitor, Aprepitant, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Aprepitant is initiated, discontinued or dose changed.
Paclitaxel	Aprepitant may change levels of the chemotherapy agent, paclitaxel.
Triazolam	Aprepitant may increase the effect and toxicity of the benzodiazepine, triazolam.
Ritonavir	This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Diltiazem	This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Acenocoumarol	Aprepitant may decrease the anticoagulant effect of acenocoumarol by decreasing its serum concentration.
Carbamazepine	The CYP3A4 inducer, carbamazepine, may decrease the effect of aprepitant.
Voriconazole	Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of aprepitant by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of aprepitant if voriconazole is initiated, discontinued or dose changed.
Telithromycin	Telithromycin may reduce clearance of Aprepitant. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Aprepitant if Telithromycin is initiated, discontinued or dose changed.
Nelfinavir	This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Tramadol	Aprepitant may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.
Ifosfamide	Aprepitant may change levels of the chemotherapy agent, ifosfamide.
Alprazolam	Aprepitant may increase the effect and toxicity of the benzodiazepine, alprazolam.
Vincristine	Aprepitant may change levels of the chemotherapy agent, vincristine.
Pimozide	Increased risk of cardiotoxicity and arrhythmias
Terfenadine	Increased risk of cardiotoxicity and arrhythmias
Dexamethasone	Aprepitant may increase the effect and toxicity of dexamethasone.
Rifampin	The CYP3A4 inducer, rifampin, may decrease the effect of aprepitant.
Warfarin	Aprepitant may decrease the anticoagulant effect of warfarin by decreasing its serum concentration.
Astemizole	Increased risk of cardiotoxicity and arrhythmias
Mestranol	Aprepitant could decrease the effect of the oral contraceptive
Ethinyl Estradiol	Aprepitant could decrease the effect of the oral contraceptive
Fosphenytoin	The CYP3A4 inducer, fosphenytoin, may decrease the effect of aprepitant.
Irinotecan	Aprepitant may change levels of the chemotherapy agent, irinotecan.
Corticotropin	Aprepitant may increase the serum concentration of Corticosteroids (Systemic). Monitor for increased effects of systemic corticosteroids when coadmininistered with aprepitant; corticosteroid dose reduction may be necessary. The manufacturer of fosaprepitant (a prodrug of aprepitant) states that oral dexamethasone doses should be reduced by 50% when coadministered with a fosaprepitant/aprepitant regimen to achieve dexamethasone concentrations similar to those achieved with dexamethasone alone. Dexamethasone doses used in clinical chemotherapy nausea/vomiting studies with aprepitant reflect this 50% decrease. Similarly, it is recommended that in order to achieve concentrations similar to those achieved with methylprednisolone alone, the intravenous methylprednisolone dose should be reduced by 25% and the oral methylprednisolone dose should be reduced by 50% when given together with a fosaprepitant/aprepitant regimen.
Erythromycin	Erythromycin, a moderate CYP3A4 inhibitor, may increase the effect and toxicity of aprepitant.
Vinblastine	Aprepitant may change levels of the chemotherapy agent, vinblastine.
Mephenytoin	The CYP3A4 inducer, mephenytoin, may decrease the effect of aprepitant.
Ketoconazole	This CYP3A4 inhibitor increases the effect and toxicity of aprepitant
Imatinib	Aprepitant may change levels of the chemotherapy agent, imatinib.
Cisapride	Increased risk of cardiotoxicity and arrhythmias
Ethotoin	The CYP3A4 inducer, ethotoin, may decrease the effect of aprepitant.
Methylprednisolone	Increases the effect and toxicity of methylprednisolone

show less «

Targets

Substance-P receptor

This is a receptor for the tachykinin neuropeptide substance P. It is probably associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is:substance P > substance K > neuromedin K

UniProt ID:

P25103

Gene:

TACR1

Actions:

antagonist

References:

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5.
View Article

Brands KM, Payack JF, Rosen JD, Nelson TD, Candelario A, Huffman MA, Zhao MM, Li J, Craig B, Song ZJ, Tschaen DM, Hansen K, Devine PN, Pye PJ, Rossen K, Dormer PG, Reamer RA, Welch CJ, Mathre DJ, Tsou NN, McNamara JM, Reider PJ: Efficient synthesis of NK(1) receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation. J Am Chem Soc. 2003 Feb 26;125(8):2129-35.
View Article

Rodgers J, Bradley B, Kennedy PG: Combination chemotherapy with a substance P receptor antagonist (aprepitant) and melarsoprol in a mouse model of human African trypanosomiasis. Parasitol Int. 2007 Dec;56(4):321-4. Epub 2007 Jun 29.
View Article

Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, Julie Ma G, Eldridge K, Hipple A, Evans JK, Horgan KJ, Lawson F: Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer. 2003 Jun 15;97(12):3090-8.
View Article

Zhao MM, McNamara JM, Ho GJ, Emerson KM, Song ZJ, Tschaen DM, Brands KM, Dolling UH, Grabowski EJ, Reider PJ, Cottrell IF, Ashwood MS, Bishop BC: Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction. J Org Chem. 2002 Sep 20;67(19):6743-7.
View Article

Bergstrom M, Hargreaves RJ, Burns HD, Goldberg MR, Sciberras D, Reines SA, Petty KJ, Ogren M, Antoni G, Langstrom B, Eskola O, Scheinin M, Solin O, Majumdar AK, Constanzer ML, Battisti WP, Bradstreet TE, Gargano C, Hietala J: Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biol Psychiatry. 2004 May 15;55(10):1007-12.
View Article

Enzymes

DrugBank

Identification

Name:	aprepitant
Name (isomeric):	DB06717
Drug Type:	small molecule
Brand:	Emend® IV
Category:	Antiemetics
CAS number:	172673-20-0

Pharmacology

Indication:	For the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy.
Pharmacology:	Fosaprepitant is a prodrug of Aprepitant. Once biologically activated, the drug acts as a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.... show more » Fosaprepitant is a prodrug of Aprepitant. Once biologically activated, the drug acts as a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT₃), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV). show less «
Mechanism of Action:	Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepit... show more » Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepitant augments 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 emesis. In summary, the active form of fosaprepitant is as an NK1 antagonist which is because it blocks signals given off by NK1 receptors. This therefore decreases the likelihood of vomiting in patients experiencing. show less «
Protein binding:	95% +
Biotransformation:	Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.
Route of elimination:	Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk.
Half Life:	9-13 hours

Interactions

Drug interaction:

Corticotropin

Fosaprepitant may increase the serum concentration of Corticosteroids (Systemic). The active metabolite aprepitant is likely responsible for this effect. The manufacturer of fosaprepitant states that oral dexamethasone doses should be reduced by 50% when coadministered with a fosaprepitant/aprepitant regimen to achieve dexamethasone concentrations similar to those achieved with dexamethasone alone.1 Dexamethasone doses used in clinical chemotherapy nausea/vomiting studies with aprepitant reflect this 50% decrease. Similarly, it is recommended that in order to achieve concentrations similar to those achieved with methylprednisolone alone, the intravenous methylprednisolone dose should be reduced by 25% and the oral methylprednisolone dose should be reduced by 50% when given together with a fosaprepitant/aprepitant regimen. Monitor for increased effects of systemic corticosteroids when coadmininistered with fosaprepitant or aprepitant.

Targets

Enzymes