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Chapter: Basic & Clinical Pharmacology : Immunopharmacology

Mammalian Target Of Rapamycin (mTOR) Inhibitors

The mTOR inhibitors include sirolimus (rapamycin) as well as its analogs (called “rapalogs”) such as everolimus and temsirolimus.


The mTOR inhibitors include sirolimus (rapamycin) as well as its analogs (called “rapalogs”) such as everolimus and temsirolimus.

Sirolimus is an immunosuppressant macrolide antibiotic produced by Streptomyces hygroscopicus and is structurally similar to tacroli-mus. Sirolimus binds the circulating immunophilin FK506-binding protein 12, resulting in an active complex that inhibits the kinase activity of mammalian target of rapamycin (mTOR). The mTOR is a key component of a complex intracellular signaling pathway involved in cellular processes such as cell growth and proliferation, angiogenesis, and metabolism. Thus, blockade of mTOR ultimately can, for example, lead to inhibition of interleukin-driven T-cell proliferation. The signaling pathways involved in mTor are an active area of investigation in immunotherapy and targeted cancer therapy. Sirolimus is available only as an oral drug. Its half-life is about 60 hours, while that of everolimus is about 43 hours. Both drugs are rapidly absorbed and elimination is similar to that of cyclosporine and tacrolimus, being substrates for both cytochrome P450 3A and P-glycoprotein. Hence, significant drug interactions can occur. For example, use with cyclosporine can increase the plasma levels of both sirolimus and everolimus such that drug levels need to be monitored. The target dose-range of these drugs will vary depending on clinical use.

Sirolimus has been used effectively alone and in combination with other immunosuppressants (corticosteroids, cyclosporine, tacrolimus, and mycophenolate mofetil) to prevent rejection of solid organ allografts. It is used as prophylaxis and as therapy for steroid-refractory acute and chronic graft-versus-host disease in hematopoietic stem cell transplant recipients. Topical sirolimus is also used in some dermatologic disorders and, in combination with cyclosporine, in the management of uveoretinitis. Recently, sirolimus-eluting coronary stents have been shown to reduce rest-enosis and other adverse cardiac events in patients with severe coronary artery disease. These benefits appear to be due to its antiproliferative effects. Everolimus is a rapalog with better bio-availability than sirolimus, but it appears that its clinical efficacy is similar to sirolimus in solid organ transplant recipients. Temsirolimus is not currently used as an immunosuppressant. Both temsirolimus and everolimus are used and being investigated as targeted therapy for various cancers.

Toxicities of the mTOR inhibitors can include profound myelosuppression (especially thrombocytopenia), hepatotoxicity, diarrhea, hypertriglyceridemia, pneumonitis, and headache. Because nephrotoxicity is of major concern when administering calcineurin inhibitors, sirolimus is frequently employed as first-line immunosuppressant therapy in both solid organ and stem cell transplantation because renal toxicity is usually not seen. However, increased use in stem cell transplantation regimens as graft-versus-host disease prophylaxis, particularly when combined with tacrolimus, has revealed an increased incidence of hemolyt-ic-uremic syndrome.

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