Article: Sirolimus

Sirolimus
Systematic (IUPAC) name
[3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*, 19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5, 19-dihydroxy-3- [2-(4-hydroxy-3-methoxycyclohexyl) -1-methylethenyl]-14, 16-dimethoxy-4,10,12, 18-tetramethyl-8-(2-propenyl)-15, 19-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclotricosine-1,7,20, 21(4H,23H)-tetrone, monohydrate.
Identifiers
CAS number	53123-88-9
ATC code	L04AA10
PubChem	6436030
DrugBank	APRD00178
Chemical data
Formula	C51H79NO13
Mol. weight	914.172 g/mol
Pharmacokinetic data
Bioavailability	20%, less after eating food rich in fat
Protein binding	92%
Metabolism	Hepatic
Half life	57-63 hours
Excretion	Mostly faecal
Therapeutic considerations
Pregnancy cat.	C
Legal status
Routes	Intravenous, oral, cutaneously

Sirolimus is a relatively new immunosuppressant drug used to prevent rejection in organ transplantation, and is especially useful in kidney transplants. It is also known as rapamycin. Sirolimus is a macrolide antibiotic ("-mycin") first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from an island called Rapa Nui, better known as Easter Island.^[1] It is marketed as Rapamune® by Wyeth.

Interestingly, rapamycin originally was developed as an antifungal agent. However, this was abandoned when it was discovered that rapamycin had potent immunosuppressive and antiproliferative properties.

Mechanism of action

Despite its similar name, it is not a calcineurin inhibitor like tacrolimus or ciclosporin. However, it has a similar suppressive effect on the immune system. Sirolimus inhibits the response to IL-2 and thereby blocks activation of T- and B-cells. In contrast, tacrolimus and cyclosporine inhibit the production of IL-2.

The mode of action of sirolimus is that it binds to the cytosolic protein FK-binding protein 12 (FKBP12), in a similar way to tacrolimus. However, unlike the tacrolimus-FKBP12 complex which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin (mTOR) pathway through derepression of PP2A, resulting in inhibition of lymphocyte proliferation.

Use in transplant

The chief advantage sirolimus over calcineurin inhibitors is that it is not toxic to kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even chronic renal failure, and this can be prevented by use of sirolimus instead. It is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used.

Sirolimus can also be used alone or in conjuction with calcineurin inhibitors and/or mycophenolate mofetil, to provide steroid-free immunosuppression regimes. As impaired wound healing is a possible side effect of sirolimus, some transplant centres prefer not to use it immediately after the transplant operation, and start to give it after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined and is the subject of a number of ongoing clinical trials.

Anti-proliferative effects

The anti-proliferative effect of sirolimus has also been used in the production of sirolimus-eluting stents used to treat obstructed coronary arteries, as it is believed that sirolimus-eluting stents are less likely to cause intimal hyperplasia than ordinary stents. It is possible that this effect may also be found in other arterial stents. A sirolums-coated coronary stent is marketed by Cordis as the Cypher stent.

Cancer

The anti-proliferative effects of sirolimus may have a role in treating cancer. Recently, it was shown that sirolimus inhibited the progression of dermal Kaposi's sarcoma in patients with renal transplants. Other mTOR inhibitors such as temsirolimus (CCI-779) or everolimus (RAD001) are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma.

Combination therapy of doxorubicin and rapamycin (Sirolimus) has been shown to drive AKT-positive lymphomas into remission in mice. Akt signalling promotes cell survival in Akt-positive lymphomas and acts to prevent the cytotoxic effects of chemotherapy drugs like doxorubicin or cyclophosphamide. Rapamycin blocks Akt signalling and the cells lose their resistance to the chemotherapy. Bcl-2-positive lymphomas were completely resistant to the therapy; Nor are eIF4E expressing lymphomas sensitive to Rapamycin*. Rapamycin showed no effect on its own. [2], [3],[4],[5], *[6]