Description
Everolimus(159351-69-6), an oral immunosuppressant for the treatment of kidney and heart transplant rejection, is the 40-O-(2-hydroxyethyl) derivative of rapamycin. It has immunosuppressive properties similar to those of rapamycin, but with improved pharmacokinetic profile. Everolimus, like rapamycin, is a proliferation signal inhibitor that exerts its immunosuppressive effect by inhibiting the activation of p70 S6 kinase, thereby blocking growth factor-driven proliferation of T cells, B cells and vascular smooth muscle cells, and arresting cell cycle at the G1 phase. Inhibition of p70 S6 kinase activation by everolimus and rapamycin is mediated by their binding to FKBP12 (FK506 binding-protein 12). Everolimus inhibits FK506 binding to FKBP12 with an IC50 of 1.8–2.6 nM, and it is about 3- to 5-fold less potent than rapamycin (IC50=0.4–0.9 nM). The in vitro immunosuppressive activity of everolimus is also slightly less than that of rapamycin as demonstrated in a mixed lymphocyte reaction (MLR) assay (IC50=0.2–1.6 nM versus 0.07–0.5 nM, respectively) and in antigen-specific human helper T-cell clones (IC50=0.05–0.17nM versus 0.014–0.37nM, respectively). However, the in vivo immunosuppressive activity of oral everolimus 1–5 mg/ kg/day is similar to that of rapamycin at equivalent doses in rat models of renal or cardiac transplantation, localized graft-versus-host disease, and autoimmune glomerulonephritis. The recommended dosage of everolimus is 0.75 mg twice daily, and it is used in combination with cyclosporine microemulsion and corticosteroids.
Chemical Properties
Off White Solid
Originator
Novartis (Switzerland)
Uses
Everolimus (IX) (SDZ-RAD), was developed by
Novartis as an immunosuppressant to be used in
conjunction with cyclosporin in transplantation allograft
rejection and was recently approved in the US in 2003.
Another natural product that had been approved for use in
transplantation is rapamycin (sirolimus) as an inejectable
agent. In an attempt to develop an orally bioavailable immunosuppressant agent, many companies attempted
modification of rapamycin itself.
Uses
Everolimus is a semi-synthetic macrocyclic lactone prepared from rapamycin by selective alkylation of the 42-hydroxy group with a silyl-protected hydroxyethyl triflate moiety, followed by addition of an ethylhydroxy moiety to provide greater stability and bioavailability. Like all tacrolimus analogues, everolimus binds to receptor protein, FKBP12. The complex then binds to mTOR preventing it from interacting with target proteins. Everolimus is extensively cited in the literature with over 2,000 citations.
Uses
Macrolide immunosuppressant; derivative of Rapamycin. Inhibits cytokine-mediated lymphocyte proliferation
Definition
ChEBI: Everolimus is a macrocyclic lactone that is rapamycin in which the hydroxy group attached to the cyclohexyl moiety has been converted into the corresponding 2-hydroxyethyl ether. It is an immunosuppressant and antineoplastic agent. It has a role as an antineoplastic agent, an immunosuppressive agent, a mTOR inhibitor, an anticoronaviral agent and a geroprotector. It is a primary alcohol, a secondary alcohol, an ether, a cyclic ketone, a cyclic acetal and a macrolide lactam. It is functionally related to a member of sirolimus.
General Description
Everolimus, sold under trade names including Zortress?, Certican, and Afinitor?, is an immunosuppressant drug used to prevent rejection of organ transplants and to treat renal cell cancer and other tumors. This Certified Spiking Solution? is suitable as starting material for calibrators, controls, or linearity standards for therapeutic drug monitoring or clinical and diagnostic testing of everolimus in patient whole blood samples by LC-MS/MS.
Biological Activity
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that, as part of two distinct complexes (mTORC1 and mTORC2), plays pivotal roles in intracellular signaling. Everolimus is a hydroxyethyl ether rapamycin derivative that inhibits mTOR signaling through both mTORC1 and mTORC2 when added to cells at 20 nM. It is orally available and shows improved pharmacokinetics and pharmacodynamics over rapamycin. Through its inhibition of mTOR, everolimus inhibits cell proliferation, metabolism, and angiogenesis in certain types of cancer. It also acts as an immunosuppressive agent in the context of organ transplantation.
Biochem/physiol Actions
Everolimus, the 40-O-(2-hydroxyethyl) derivative of rapamycin (sirolimus), is a potent and selective inhibitor of mechanistic target of rapamycin (mTOR). Everolimus is selective for the mTORC1 protein complex. Everolimus exhibit potent immunosuppressive and anticancer activities.
Synthesis
Everolimus (IX) was
discovered by Sandoz (Novartis) scientists by modifying
rapamycin drug in the 40-hydroxyl position. Thus,
treatment of rapamycin (84) with t-butyldimethylsilyloxy
ethyl triflate in the presence of 2,6-lutidine at 60??C for 3.5
hrs gave ether 85. Deprotection of the silyl group was done
by treating silyloxy ether 85 in methanol with 2N HCl to
give the product IX (everolimus), which was purified by
chromatography. No yields were given for the reactions.
Drug interactions
Potentially hazardous interactions with other drugs
ACE-Is: increased risk of angioedema.
Antibacterials: erythromycin, clarithromycin and
telithromycin increase everolimus levels - avoid
with clarithromycin and telithromycin; rifampicin
decreases everolimus levels by factor of 3.
Antidepressants: St John’s wort decreases everolimus
levels.
Antifungals: concentration increased by ketoconazole
and possibly itraconazole, posaconazole and
voriconazole - avoid.
Antipsychotics: increased risk of agranulocytosis
with clozapine - avoid.
Antivirals: concentration possibly increased by
atazanavir, darunavir, indinavir, ritonavir and
saquinavir - avoid; concentration significantly
increased by dasabuvir and ombitasvir/paritaprevir/
ritonavir - avoid concomitant use.
Calcium channel blockers: concentration of both
drugs increased with verapamil.
Ciclosporin: increases everolimus AUC by 168% and
Cmax by 82%.
Cytotoxics: concentration increased by imatinib -
consider reducing everolimus dose.
Grapefruit juice: increases everolimus levels.
Metabolism
Everolimus(159351-69-6) is metabolised in the liver and to some extent in the gastrointestinal wall, and is a substrate of P-glycoprotein and the cytochrome P450 isoenzyme CYP3A4. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ringopened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were shown to have approximately 100 times less activity than everolimus itself. Following the administration of a single dose of radiolabelled everolimus, 80% of the radioactivity was recovered from the faeces, while 5% was excreted in the urine. The parent substance was not detected in urine or faeces.
