Sirolimus
Macrolide immunosuppressant that inhibits mTOR to block T-cell proliferation in transplant rejection and coronary stent coatings.
Chemical Identity
| Property | Value |
|---|---|
| Chemical Formula | C51H79NO13 |
| Molecular Weight | 914.17 Da |
| CAS Number | 53123-88-9 |
| Peptide Class | Macrolide (Polyketide-Peptide Hybrid) |
| Origin | Streptomyces hygroscopicus |
Structure
Sirolimus (rapamycin) is a 31-membered macrolide produced by Streptomyces hygroscopicus, first isolated from soil samples on Easter Island (Rapa Nui). It contains a pipecolic acid moiety and an unusual triene system. The molecule is structurally related to tacrolimus, sharing the FKBP12-binding domain but with an extended macrocyclic ring.
Mechanism of Action
Sirolimus binds to FKBP12, and the sirolimus-FKBP12 complex directly inhibits mTOR (mechanistic target of rapamycin) complex 1 (mTORC1). This blocks IL-2-mediated signal transduction, preventing T-cell progression from G1 to S phase. Unlike calcineurin inhibitors, sirolimus acts distal to cytokine receptor signaling.
Clinical Applications
- Kidney transplant: Prevention of rejection (often with cyclosporine)
- Coronary stents: Drug-eluting stent coating to prevent restenosis
- Lymphangioleiomyomatosis: First-line therapy
- Tuberous sclerosis: Renal angiomyolipomas and SEGAs
Pharmacokinetics
- Half-life: 62 hours
- Tmax: 1-2 hours (oral solution)
- Bioavailability: 14% (tablet), 21% (solution)
- Metabolism: CYP3A4 and P-glycoprotein substrate
- Protein binding: 92%
- Route: Oral, IV (stent coating)
Safety and Side Effects
Thrombocytopenia, hyperlipidemia (hypertriglyceridemia), delayed wound healing, oral ulcers, acne, pneumonitis, and increased infection risk. Does not cause nephrotoxicity like calcineurin inhibitors.
References
- Sehgal, S.N. (2003). Sirolimus: from Easter Island to clinical practice. Expert Opinion on Pharmacotherapy, 4, 1327-1343.
- Kahan, B.D. (2000). Sirolimus: a new agent for clinical transplantation. Transplantation Proceedings, 32, 2230-2233.
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