Aprepitant
Encyclopedia
Aprepitant is an antiemetic
chemical compound that belongs to a class of drugs called substance P
antagonists (SPA). It mediates its effect by blocking the neurokinin 1 (NK1) receptor.
Aprepitant is manufactured by Merck & Co.
under the brand name Emend for prevention of acute and delayed chemotherapy-induced nausea and vomiting
(CINV) and for prevention of postoperative nausea and vomiting
. It was approved by the FDA in 2003.
Aprepitant may also be useful in the treatment of cyclic vomiting syndrome
but there are few studies to date.
On January 2008, the FDA approved fosaprepitant
, an intravenous form of aprepitant, which is to be sold under the tradename Emend Injection in the US and as Ivemend in some other countries.
, for example cisplatin
. Throughout the 1990s a noticeable increase occurred in the number of diagnosed cancer patients undergoing chemotherapy
and therefore experiencing CINV. As a result of this, toward the end of the decade, initial research was conducted to try to develop a drug that eases the severity and decreases the likelihood of CINV, and after several years of research Merck & Co.
successfully developed a drug known as Emend.
The active substance of Emend is aprepitant, which is effective in helping to prevent CINV because it antagonizes the NK1 receptor. This receptor is located at the brain stem
nuclei of the dorsal vagal complex and is a crucial part of the regulation of vomiting
. This is due to the receptor binding with substance P
, a peptide
neurotransmitter
.
core with two substituents attached to adjacent ring carbon
s. These substitute groups are trifluoromethylated phenyl ethanol and fluorophenyl group. Aprepitant also has a third substituent (triazolinone), which is joined to the morpholine ring nitrogen
. This means that aprepitant is made up of three chiral centres very close together, which combine to produce an amino acetal
arrangement. It also means that the empirical formula
of the substance is C23H21F7N4O3.
Aprepitant is an off-white crystalline solid
that has a molecular weight of around 534.53. It has a very limited solubility
in water. It does have a reasonable high solubility in non-polar molecules such as oils. This would, therefore, suggest that aprepitant as a whole, despite having components that are polar, is a non-polar substance.
, dimethyltitanocene, and gaseous ammonia. In addition to this, for the process to be effective cryogenic temperatures were needed for some of the steps and other steps produced hazardous by products such as methane and magnesium chloride
. The environmental concerns of the synthesis of aprepitant became so great that Merck research team decide to withdraw the drug from clinical trials and attempt to create a different synthesis of aprepitant.
The gamble of taking the drug out of clinical trials proved to be successful when shortly afterwards the team of Merck researchers came up with an alternative and more environmentally friendly synthesis of aprepitant. The new process works by four compounds of similar size and complexity being fused together. This therefore is a much simpler process and requires only three steps, half the number of the original synthesis.
The new process begins by enantiopure trifluoromethylated phenyl ethanol (Red) being joined to a racemic morpholine precursor (Blue). This results in the wanted isomer
crystallizing on the top of the solution and the unwanted isomer remaining in the solution. The unwanted isomer is then converted to the wanted one by the chemist controlling the reaction conditions and a process known as crystallization-induced asymmetric transformation occurring. By the end of this step a secondary amine
, the base of the drug, is formed.
The second step involves the fluorophenyl group (Black) being attached to the morpholine ring (Blue). Once this has been achieved the third and final step can initiated. This step involved a side chain of triazolinone being added (Green) to the ring. Once this step has been successfully completed a stable molecule of aprepitant has been produced.
This more streamlined route not only yields around 76% more aprepitant than the original process but also reduces the operating cost by a significant amount. In addition to this the new process also reduces the amount of solvent and reagents required by about 80% and saved an estimated 340,000L per a ton of aprepitant produced.
As a result of the improvements in the efficiency and reduction of environmental impacts of the synthesis of aprepitant, several social benefits have occurred. The most noticeable of which is a reduction in the price of the drug. This has resulted in a greater number of patients having access to it, which therefore has caused a decrease in the number of people that undergo chemotherapy experiencing CINV. The improvements in the synthesis process have also resulted in a decrease in the number long-term detrimental to the natural environment, due to elimation of hazardous chemicals from the procedure.
Researches began to analyse aprepitant and make observations about its chemical and physical properties. It was discovered that the substance has a low aqueous solubility. As a result of this the product development focused on reducing the size of aprepitant’s particles to a nanoscale. This therefore would increase the bioavailability of the drug.
Using this information Merck came up with a manufacturing process, (which is still used today). This nine step process includes wet milling, which reduces the particle size of the active ingredient. It also involves excipients being used to keep the nanoparticle
s of aprepitant separated from each other during and after the microcrystalline celluse beads being coated. This therefore prevents agglomerating of the beads, which means that nanoparticles of aprepitant remains small even after it is re dispersed from the beads.
The nine-step manufacturing process involves
The end result of the nine step process is a capsule, known as Emend, which contain aprepitant. The capsule also contains several other substances, which includes sucrose, hydroxypropyl cellulose, microcrystalline cellulose
, sodium lauryl sulfate, gelatin
, shellac
, black iron oxide
and titanium dioxide
.
because it blocks signals given off by NK1 receptors. This, therefore, decreases the likelihood of vomiting in patients. Emend is usually taken as a preventative for CINV, which is a serious side-effect experienced by over 80% of patients who undergo chemotherapy.
NK1 is a G protein-coupled receptor
and is located in the central nervous system and the peripheral nervous system. This receptor has a dominant ligand known as Substance P (SP). SP is a neuropeptide
, composed of 11 amino acids, which sends and receives impulses and messages from the brain. It is found in high concentrations in the vomiting center of the brain, and, when activated, it results in a vomiting reflux occurring. In addition to this it also plays a key part in the transmission of pain impulses from the peripheral receptors to the central nervous system.
Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic drugs by blocking substance P landing on receptors in the brains neurons. This has been proven by Positron Emission Tomography
(PET) studies, which have demonstrated that aprepitant can penetrate the brain and NK1 receptors in the brain. It has also been shown to increase the activity of the 5-HT3 receptor
antagonists ondansetron
and the corticosteroid dexamethasone
, which are also used to prevent nausea and vomiting caused by chemotherapy.
Aprepitant is taken orally in the form of a capsule. Before clinical testing, a new class of therapeutic agent has to be characterized in terms of preclinical metabolism and excretion studies. Average bioavailability
is found to be around 60-65%. 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. As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of coadministered medicinal products that are metabolized through CYP3A4. Following IV administration of a 14C-labelled prodrug of aprepitant (L-758298), which is
converted rapidly and completely to aprepitant, approximately 57% of the total radioactivity is
excreted in the urine and 45% in faeces. No unchanged substance is excreted in urine.
One of the fundamental features of aprepitant, and a major advantage it has over other chemotherapy-induced side-effect treatments, is it that- while it successfully antagonises the NK1 receptors, it has very little affinity over other receptors such as serotonin, dopamine, and corticosteroid. It is estimated that aprepitant is at least 3000 times more selective of NK1 receptors compared to these other enzyme transporter, ion channel
s.
.
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
chemical compound that belongs to a class of drugs called substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
antagonists (SPA). It mediates its effect by blocking the neurokinin 1 (NK1) receptor.
Aprepitant is manufactured by Merck & Co.
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
under the brand name Emend for prevention of acute and delayed chemotherapy-induced nausea and vomiting
Chemotherapy-induced nausea and vomiting
Chemotherapy-induced nausea and vomiting is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy ranked nausea...
(CINV) and for prevention of postoperative nausea and vomiting
Postoperative nausea and vomiting
Postoperative nausea and vomiting is an unpleasant complication affecting about a third of the 10% of the population undergoing general anaesthesia each year. This equates to about two million people in the United Kingdom annually.-Impact:...
. It was approved by the FDA in 2003.
Aprepitant may also be useful in the treatment of cyclic vomiting syndrome
Cyclic vomiting syndrome
Cyclic vomiting syndrome or cyclical vomiting syndrome is a condition whose symptoms are recurring attacks of intense nausea, vomiting and sometimes abdominal pain and/or headaches or migraines...
but there are few studies to date.
On January 2008, the FDA approved fosaprepitant
Fosaprepitant
Fosaprepitant is an antiemetic drug, administered intravenously. It is a prodrug of aprepitant....
, an intravenous form of aprepitant, which is to be sold under the tradename Emend Injection in the US and as Ivemend in some other countries.
Initial development
Acute or delayed CINV is an unpleasant side effect experienced by over 80% of patients undergoing initial and repeated highly emetogenic cancer chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, for example cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
. Throughout the 1990s a noticeable increase occurred in the number of diagnosed cancer patients undergoing chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
and therefore experiencing CINV. As a result of this, toward the end of the decade, initial research was conducted to try to develop a drug that eases the severity and decreases the likelihood of CINV, and after several years of research Merck & Co.
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
successfully developed a drug known as Emend.
The active substance of Emend is aprepitant, which is effective in helping to prevent CINV because it antagonizes the NK1 receptor. This receptor is located at the brain stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
nuclei of the dorsal vagal complex and is a crucial part of the regulation of vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
. This is due to the receptor binding with substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
, a peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
.
Structure and properties of aprepitant
Aprepitant is made up of a morpholineMorpholine
Morpholine is an organic chemical compound having the chemical formula O2NH. This heterocycle, pictured at right, features both amine and ether functional groups. Because of the amine, morpholine is a base; its conjugate acid is called morpholinium...
core with two substituents attached to adjacent ring carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
s. These substitute groups are trifluoromethylated phenyl ethanol and fluorophenyl group. Aprepitant also has a third substituent (triazolinone), which is joined to the morpholine ring nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
. This means that aprepitant is made up of three chiral centres very close together, which combine to produce an amino acetal
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
arrangement. It also means that the empirical formula
Empirical formula
In chemistry, the empirical formula of a chemical compound is the simplest positive integer ratio of atoms of each element present in a compound. An empirical formula makes no reference to isomerism, structure, or absolute number of atoms. The empirical formula is used as standard for most ionic...
of the substance is C23H21F7N4O3.
Aprepitant is an off-white crystalline solid
Solid
Solid is one of the three classical states of matter . It is characterized by structural rigidity and resistance to changes of shape or volume. Unlike a liquid, a solid object does not flow to take on the shape of its container, nor does it expand to fill the entire volume available to it like a...
that has a molecular weight of around 534.53. It has a very limited solubility
Solubility
Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on...
in water. It does have a reasonable high solubility in non-polar molecules such as oils. This would, therefore, suggest that aprepitant as a whole, despite having components that are polar, is a non-polar substance.
Synthesis
Shortly after Merck initiated research into the reducing the severity and likelihood of CINV, researchers discovered that aprepitant is effective in prevention. Researchers worked on coming up with a process to create aprepitant, and within a short period they came up with effective synthesis of the substance. This original synthesis was deemed to be workable and proved to be a crucial step in achieving commercialization; however, Merck decided that the process was not environmentally sustainable. This was due to the original synthesis requiring six steps, many of which needed dangerous chemicals such as sodium cyanideSodium cyanide
Sodium cyanide is an inorganic compound with the formula NaCN. This highly toxic colorless salt is used mainly in gold mining but has other niche applications...
, dimethyltitanocene, and gaseous ammonia. In addition to this, for the process to be effective cryogenic temperatures were needed for some of the steps and other steps produced hazardous by products such as methane and magnesium chloride
Magnesium chloride
Magnesium chloride is the name for the chemical compounds with the formulas MgCl2 and its various hydrates MgCl2x. These salts are typical ionic halides, being highly soluble in water. The hydrated magnesium chloride can be extracted from brine or sea water...
. The environmental concerns of the synthesis of aprepitant became so great that Merck research team decide to withdraw the drug from clinical trials and attempt to create a different synthesis of aprepitant.
The gamble of taking the drug out of clinical trials proved to be successful when shortly afterwards the team of Merck researchers came up with an alternative and more environmentally friendly synthesis of aprepitant. The new process works by four compounds of similar size and complexity being fused together. This therefore is a much simpler process and requires only three steps, half the number of the original synthesis.
The new process begins by enantiopure trifluoromethylated phenyl ethanol (Red) being joined to a racemic morpholine precursor (Blue). This results in the wanted isomer
Isomer
In chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
crystallizing on the top of the solution and the unwanted isomer remaining in the solution. The unwanted isomer is then converted to the wanted one by the chemist controlling the reaction conditions and a process known as crystallization-induced asymmetric transformation occurring. By the end of this step a secondary amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
, the base of the drug, is formed.
The second step involves the fluorophenyl group (Black) being attached to the morpholine ring (Blue). Once this has been achieved the third and final step can initiated. This step involved a side chain of triazolinone being added (Green) to the ring. Once this step has been successfully completed a stable molecule of aprepitant has been produced.
This more streamlined route not only yields around 76% more aprepitant than the original process but also reduces the operating cost by a significant amount. In addition to this the new process also reduces the amount of solvent and reagents required by about 80% and saved an estimated 340,000L per a ton of aprepitant produced.
As a result of the improvements in the efficiency and reduction of environmental impacts of the synthesis of aprepitant, several social benefits have occurred. The most noticeable of which is a reduction in the price of the drug. This has resulted in a greater number of patients having access to it, which therefore has caused a decrease in the number of people that undergo chemotherapy experiencing CINV. The improvements in the synthesis process have also resulted in a decrease in the number long-term detrimental to the natural environment, due to elimation of hazardous chemicals from the procedure.
Drug development
Once the effective synthesis of aprepitant was discovered, the next step taken by Merck was to develop a pharmaceutical drug that incorporates the active substance in it.Researches began to analyse aprepitant and make observations about its chemical and physical properties. It was discovered that the substance has a low aqueous solubility. As a result of this the product development focused on reducing the size of aprepitant’s particles to a nanoscale. This therefore would increase the bioavailability of the drug.
Using this information Merck came up with a manufacturing process, (which is still used today). This nine step process includes wet milling, which reduces the particle size of the active ingredient. It also involves excipients being used to keep the nanoparticle
Nanoparticle
In nanotechnology, a particle is defined as a small object that behaves as a whole unit in terms of its transport and properties. Particles are further classified according to size : in terms of diameter, coarse particles cover a range between 10,000 and 2,500 nanometers. Fine particles are sized...
s of aprepitant separated from each other during and after the microcrystalline celluse beads being coated. This therefore prevents agglomerating of the beads, which means that nanoparticles of aprepitant remains small even after it is re dispersed from the beads.
The nine-step manufacturing process involves
- A slurry of aprepitant, hydroxypropyl celluloseHydroxypropyl celluloseHydroxypropyl cellulose is a derivative of cellulose with both water solubility and organic solubility. It is used as a topical ophthalmic protectant and lubricant.-Chemistry:...
, and water being produced - The slurry undergoing pre-milling
- An aqueous sucrose dispersion being added to the slurry
- The slurry undergoing media-milling that produces a colloidal dispersion
- An aqueous sucroseSucroseSucrose is the organic compound commonly known as table sugar and sometimes called saccharose. A white, odorless, crystalline powder with a sweet taste, it is best known for its role in human nutrition. The molecule is a disaccharide composed of glucose and fructose with the molecular formula...
dispersion being added to the slurry - The microcrystalline cellulose beads being spray coated with the colloidal dispersion.
- The coated beads being sieved
- The coated microcrystalline cellulose beads are blended with micronised sodium lauryl sulfate
- The blended beads are encapsulated
The end result of the nine step process is a capsule, known as Emend, which contain aprepitant. The capsule also contains several other substances, which includes sucrose, hydroxypropyl cellulose, microcrystalline cellulose
Microcrystalline cellulose
Microcrystalline cellulose is a term for refined wood pulp and is used as a texturizer, an anti-caking agent, a fat substitute, an emulsifier, an extender, and a bulking agent in food production. The most common form is used in vitamin supplements or tablets...
, sodium lauryl sulfate, gelatin
Gelatin
Gelatin is a translucent, colorless, brittle , flavorless solid substance, derived from the collagen inside animals' skin and bones. It is commonly used as a gelling agent in food, pharmaceuticals, photography, and cosmetic manufacturing. Substances containing gelatin or functioning in a similar...
, shellac
Shellac
Shellac is a resin secreted by the female lac bug, on trees in the forests of India and Thailand. It is processed and sold as dry flakes , which are dissolved in ethyl alcohol to make liquid shellac, which is used as a brush-on colorant, food glaze and wood finish...
, black iron oxide
Iron oxide
Iron oxides are chemical compounds composed of iron and oxygen. All together, there are sixteen known iron oxides and oxyhydroxides.Iron oxides and oxide-hydroxides are widespread in nature, play an important role in many geological and biological processes, and are widely utilized by humans, e.g.,...
and titanium dioxide
Titanium dioxide
Titanium dioxide, also known as titanium oxide or titania, is the naturally occurring oxide of titanium, chemical formula . When used as a pigment, it is called titanium white, Pigment White 6, or CI 77891. Generally it comes in two different forms, rutile and anatase. It has a wide range of...
.
Mechanism of action
Aprepitant is classified as an NK1 antagonistAntagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
because it blocks signals given off by NK1 receptors. This, therefore, decreases the likelihood of vomiting in patients. Emend is usually taken as a preventative for CINV, which is a serious side-effect experienced by over 80% of patients who undergo chemotherapy.
NK1 is a G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
and is located in the central nervous system and the peripheral nervous system. This receptor has a dominant ligand known as Substance P (SP). SP is a neuropeptide
Neuropeptide
Neuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...
, composed of 11 amino acids, which sends and receives impulses and messages from the brain. It is found in high concentrations in the vomiting center of the brain, and, when activated, it results in a vomiting reflux occurring. In addition to this it also plays a key part in the transmission of pain impulses from the peripheral receptors to the central nervous system.
Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic drugs by blocking substance P landing on receptors in the brains neurons. This has been proven by Positron Emission Tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
(PET) studies, which have demonstrated that aprepitant can penetrate the brain and NK1 receptors in the brain. It has also been shown to increase the activity of the 5-HT3 receptor
5-HT3 receptor
The 5-HT3 receptor is a member of the superfamily of ligand-gated ion channels, a superfamily that also includes the neuronal nicotinic acetylcholine receptors , and the inhibitory neurotransmitter receptors for GABA and glycine...
antagonists ondansetron
Ondansetron
Ondansetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic , often following chemotherapy. Its effects are thought to be on both peripheral and central nerves...
and the corticosteroid dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
, which are also used to prevent nausea and vomiting caused by chemotherapy.
Aprepitant is taken orally in the form of a capsule. Before clinical testing, a new class of therapeutic agent has to be characterized in terms of preclinical metabolism and excretion studies. Average bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
is found to be around 60-65%. 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. As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of coadministered medicinal products that are metabolized through CYP3A4. Following IV administration of a 14C-labelled prodrug of aprepitant (L-758298), which is
converted rapidly and completely to aprepitant, approximately 57% of the total radioactivity is
excreted in the urine and 45% in faeces. No unchanged substance is excreted in urine.
One of the fundamental features of aprepitant, and a major advantage it has over other chemotherapy-induced side-effect treatments, is it that- while it successfully antagonises the NK1 receptors, it has very little affinity over other receptors such as serotonin, dopamine, and corticosteroid. It is estimated that aprepitant is at least 3000 times more selective of NK1 receptors compared to these other enzyme transporter, ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s.
Other uses
Merck & Co. conducted clinical trials on aprepitant as a treatment of major depressive disorder, and received negative results. The company has since abandoned plans to market aprepitant as an antidepressantAntidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
.
External links
- Emend (manufacturer's website)
- Aprepitant (patient information)
- Emend (PDF prescription information)