cyclosporine
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| cyclosporine | |
|---|---|
| IUPAC name | CycloL-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-aminobutyryl-L-α-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl |
| Tradename | Sandimmune, Neoral, others |
| Drugs.com | Monograph |
| MedlinePlus | a601207 |
| Licence US | Sandimmune |
| Routes of administration | Oral, intravenous |
| CAS number | 59865-13-3 |
| PubChem | 5284373 |
| DrugBank | DB00091 |
| ChemSpiderID | 4447449 |
| UNII | 83HN0GTJ6D |
| ChEBI | 4031 |
| ChEMBL | 91 |
| NIAID ChemDB | 000644 |
| ATC prefix | L04 |
| ATC suffix | AD01 |
| ATC supplemental | S01XA18 |
| Legal AU | S4 |
| Legal CA | Rx-only |
| Legal UK | POM |
| Legal US | Rx-only |
| Legal EU | Rx-only |
| Legal status | Rx-only |
| Bioavailability | Variable |
| Protein bound | ~90% |
| Metabolism | CYP3A4 (liver) |
| Elimination half-life | Variable (≈ 19 hours) |
| Excretion | Bile |
cyclosporine is a critical calcineurin inhibitor used primarily to prevent organ transplant rejection. It was first isolated from the fungus Tolypocladium inflatum and revolutionized the field of transplantation medicine. The drug's introduction enabled the successful development of heart transplantation and liver transplantation programs worldwide.
Medical uses
The primary use is for prophylaxis of graft-versus-host disease following bone marrow transplantation and to prevent rejection of kidney, liver, and heart allografts. It is also used in the treatment of severe cases of psoriasis, atopic dermatitis, and rheumatoid arthritis when other therapies have failed. In ophthalmology, a topical formulation is used for severe keratoconjunctivitis sicca and to increase tear film production.
Mechanism of action
cyclosporine exerts its effect by binding to the intracellular protein cyclophilin within T-lymphocytes. This drug-protein complex then inhibits the phosphatase activity of calcineurin, a crucial enzyme for T cell activation. Inhibition of calcineurin prevents the dephosphorylation and nuclear translocation of the NFAT transcription factor. This blockade ultimately suppresses the transcription of IL-2 and other cytokine genes, halting the clonal expansion of cytotoxic T cells that drive immune rejection.
Pharmacokinetics
Following oral administration, absorption is incomplete and highly variable, influenced by bile flow and dietary fat content. The drug is extensively metabolized in the liver by the cytochrome P450 enzyme system, specifically the CYP3A4 isoenzyme. Metabolism produces numerous metabolites, some of which have minimal immunosuppressive activity. Elimination is primarily via the bile into the feces, with only minimal excretion through the kidney. Concomitant use of drugs that induce or inhibit CYP3A4, such as rifampin or ketoconazole, can drastically alter its blood concentrations.
Adverse effects
Significant adverse effects include dose-related nephrotoxicity, which can lead to irreversible kidney damage. Hypertension is also very common and often requires management with antihypertensive agents. Other notable effects include hyperlipidemia, hirsutism, gingival hyperplasia, tremor, and paresthesia. The drug also increases the risk of lymphoma and skin cancer due to its immunosuppressive nature. Therapeutic drug monitoring is essential to balance efficacy with toxicity.
History
cyclosporine was discovered in 1971 during a soil screening program by employees of the Swiss pharmaceutical company Sandoz (now Novartis) at laboratories in Basel. The fungus Tolypocladium inflatum was isolated from a soil sample collected in Hardanger Vidda, Norway. Its immunosuppressive properties were identified by Jean-François Borel. The first successful use in a human heart transplantation was by Sir Roy Calne at Papworth Hospital in Cambridge, and it was subsequently approved for use by the FDA in 1983.
Society and culture
The drug is marketed under trade names including Sandimmune and Neoral. Its development is considered one of the major milestones in modern medicine, enabling the routine success of organ transplantation. The discovery team, led by Jean-François Borel, received the Lasker-DeBakey Clinical Medical Research Award in recognition of their work. The high cost of therapy and the requirement for lifelong monitoring have been subjects of discussion within healthcare systems like the NHS and among insurers.
Category:Immunosuppressants Category:Organ transplantation Category:Pharmaceuticals