Sirolimus (formally known as rapamycin) and everolimus block the activating signal delivered by growth factors, exemplified by the interleukin–2 (IL-2) receptor, by phosphorylation of PHAS-1. After binding to FK-binding protein (FKBP) sirolimus and everolimus interact with the mammalian target of rapamycin (mTOR). PHAS-1 phosphorylation by mTOR is followed by dissociation of the eukaryotic Initiation Factor-4F (eIF-4F) from the DNA inhibiting the translation of the coding messenger RNA for key proteins required for progression through the G1 phase of the cell cycle. Arrest of the cell cycle results, thereby inhibiting the proliferation of lymphocytes. The full understanding of the mechanism of action of sirolimus is under research.
Everolimus is approved as an adjunctive agent (in combination with CSA + steroids) for the prevention of acute renal allograft rejection.
Dyslipidemia (increase in total cholesterol and triglycerides) requiring treatment with lipid-lowering drugs is a dose-related side effect of sirolimus therapy.
See also the application of other mTOR inhibitors in the section of Oncology.
I Sirolimus and tacrolimus bind to the same protein, but have different mechanisms of action. II Sirolimus and tacrolimus are both substrates for cytochrome P450 3A4.