Rapamycin (Sirolimus)


Rapamycin, also called sirolimus, is produced by Streptomyces hygroscopicus, a soil bacteria. The drug is named after the indigenous name of Eastern Island- Rapa Nui, where Rapamycin was first discovered during the 1970s in the soil samples. It acts as an antibiotic agent, immunosuppressive agent by repressing the T cell activation and proliferation through mTOR(Mammalian Target Of Rapamycin) inhibition and antineoplastic agent. It is classified as a transplant agent, available in solid and liquid oral form.

Pharmacokinetics- ADME (Absorption, Distribution, Metabolism & Excretion) of Rapamycin(sirolimus)

Absorption: Sirilomus is absorbed rapidly after being administered orally, with t max of approximately 1 hour for a single dose in healthy patients and about 2 hours for multiple quantities in renal transplant patients.

The systemic availability of orally transmitted sirolimus solution is approximately 14%, whereas the bioavailability of sirolimus administered in tablet form is 27% higher than the oral solution. The rate of absorption is decreased if the diet is of high-fat content.

Distribution: The blood-to-plasma ratio of sirolimus distribution is 36 +/- 17.9(+/- SD) in stable renal allograft recipients, which indicates that sirolimus is primarily distributed into blood elements.

Metabolism: Sirolimus is a substrate for P-glycoprotein & Cytochrome P450 IIIA4(CYP3A4). Sirolimus is widely metabolised by Hydroxylation or O-demethylation. There are seven human metabolites of sirolimus, namely 11-Hydroxy-sirolimus, 12-Hydroxy-sirolimus, 24-Hydroxy-sirolimus, 25-Hydroxy-sirolimus, 46-Hydroxy-sirolimus, 16-O-Desmethylsirolimus, 39-O-Desmethylsirolimus. 

Elimination: it may take up to 57 to 63 hours for elimination and increase to 72 hours in males. From the data, in most individuals, 91% is recovered from faeces and 2.2% from urine.

The Half-life is 57-63 hours.

The mechanism as an immunosuppressive agent

For the generation of an immunosuppressive complex in cells, sirolimus bind to immunophilin FKBP-12 (FK Binding Protein-12) to inhibit the activation of mTOR (a fundamental regulatory kinase), resulting in the inhibition of T-lymphocyte activation and proliferation as a result of antigenic and cytokine(Interleukin-2, 4, 5) stimulation and inhibition of the antibody production. 

Rapamycim(Sirolimus) and Cancer

An in-vivo study was conducted to assess the antitumor efficacy of the mTOR (mammalian target of Rapamycin) inhibitor sirolimus and compare its effect with its patented analogue temsirolimus in the head and neck squamous cell carcinoma(HNSCC) of animal models. The study results showed that the generic mTOR inhibitor sirolimus exhibited an effective antitumor property.

The mTOR activating signal pathways are observed to be mutilated in many types of cancer patients, like overexpression of mTOR kinases, proteins regulating mTOR, and Rapamycin being a natural inhibitor of the mTOR. 

The combination of lenalidomide(cancer drug), thalidomide derivative, and Rapamycin has induced a synergic apoptotic approach in myeloma cell lines and cells from cancer patients, even though lenalidomide and Rapamycin have the same properties immune modulator, and antiangiogenic they both have different mechanism pathways. 

The combination of sirolimus and doxorubicin (chemotherapy drug used for different types of cancer like breast cancer, bladder cancer, lymphoma) has shown to diminish the AKT(protein B-kinase, which plays an essential role in cell proliferation, apoptosis) lymphoma, as sirolimus inhibits Akt signalling pathway and making the cell sensitive to the chemotherapy.

Other therapeutic effects

It is observed that Rapamycin can alleviate Graft-versus-host disease (GVHD) by increasing the regulatory T-cell proliferation, cytotoxic T-cell inhibition, and hindering the differentiation of effector T cells. 

The lymphatic malformation is a superficial or deep, or mixed growth of the lymphatic vessels, where the treatment is either removing or destroying, but the chances of recurrence are high. A study showed that the application of topical Rapamycin could help in managing superficial lymphatic malformations.

As Rapamycin has immunosuppressive properties, it is recommended to treat SARS-Covid 19 infected patients to prevent or reduce the cytokine storm seen in severe cases; it has also diminished viral replication by inhibiting cell proliferation.

Side effects and Risk factors

Common side effects are diarrhoea, Constipation, Nausea, Vomiting, Stomach pain, joint pain, shaking, Acne, skin rash, Headache, trouble sleeping.

Some severe side effects may be seen; if any serious effects are observed, it is advised to tell your doctor; some of them may include muscle pain or cramps, bone pain, increased thirst or hunger, frequent urination, vision changes, hearing problems like hearing loss or ringing in the ears, unusual tiredness or weakness, fast/slow/irregular heartbeat, easy bruising or bleeding, mental/mood changes, swelling ankles or feet, severe Headache, Dizziness, stomach or abdominal pain, missed/heavy/painful periods.

Individuals on other medications are advised to check with the doctor before administering Rapamycin as some medicines/supplements can interact with Rapamycin.

It is generally advised to avoid Rapamycin during pregnancy and breastfeeding. Some studies showed that Rapamycin could pass into breast milk.