Aprepitant - Mechanism of Action

Mechanism of Action

Aprepitant is classified as an NK1 antagonist 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. Specific interaction has been demonstrated with oxycodone, where aprepitant both increased the efficacy and worsened the side effects of oxycodone; however it is unclear whether this is due to CPY3A4 inhibition or through its NK-1 antagonist action. 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 channels.