Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mTOR (mammalian Target Of Rapamycin, rapamycin being another name for sirolimus) pathway by directly binding to mTOR Complex 1 (mTORC1).mTOR has also been called FRAP (FKBP-rapamycin-associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2. Pharmacokinetics
Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump. It has an elimination half-life of 57–63 hours.The absorption of sirolimus into the blood stream from the intestine varies widely between patients, with some patients having up to eight times more exposure than others for the same dose. Drug levels are, therefore, taken to make sure patients get the right dose for their condition. This is determined by taking a blood sample before the next dose, which gives the trough level.
The results are further supported by the finding that genetically modified mice with impaired mTORC1 signalling live longer. Sirolimus has potential for widespread use as a longevity-promoting drug, with evidence pointing to its ability to prevent age-associated decline of cognitive and physical health. Due to known side effects of sirolimus, as well as inadequate evidence for optimal dosing, more research is required before sirolimus could be widely prescribed for this purpose.Sirolimus has complex effects on the immune system—while IL-12 goes up and IL-10 decreases, which suggests an immunostimulatory response, TNF and IL-6 are decreased, which suggests an immunosuppressive response. The duration of the inhibition and the exact extent to which mTORC1 and mTORC2 are inhibited play a role, but are not yet well understood. SARS-CoV-2
Rapamycin has been proposed as a treatment for severe acute respiratory syndrome coronavirus 2 insofar as its immunosuppressive effects could prevent or reduce the cytokine storm seen in very serious cases of COVID-19. Moreover, inhibition of cell proliferation by rapamycin could reduce viral replication. Atherosclerosis
Rapamycin can accelerate degradation of oxidized LDL cholesterol in endothelial cells, thereby lowering the risk of atherosclerosis. Oxidized LDL cholesterol is a major contributor to atherosclerosis. Lupus
As of 2016, studies in cells, animals, and humans have suggested that mTOR activation as process underlying systemic lupus erythematosus and that inhibiting mTOR with rapamycin may be a disease-modifying treatment. As of 2016 rapamycin had been tested in small clinical trials in people with lupus.