Cyclosporine

Chemical Identity

Property	Value
Chemical Formula	C62H111N11O12
Molecular Weight	1202.61 Da
CAS Number	59865-13-3
Peptide Class	Cyclic Undecapeptide
Origin	Tolypocladium inflatum (fungus)

Structure

Cyclosporine is a cyclic peptide of 11 amino acids, seven of which are N-methylated. It contains several unusual residues including D-alanine, (4R)-4-[(E)-2-butenyl]-4,N-dimethyl-L-threonine (MeBmt), and several N-methylated amino acids. The cyclic structure is essential for immunosuppressive activity.

Mechanism of Action

Cyclosporine binds to cyclophilin, and the cyclosporine-cyclophilin complex inhibits calcineurin, a calcium-dependent phosphatase. This prevents dephosphorylation and nuclear translocation of NFAT (nuclear factor of activated T-cells), blocking IL-2 transcription and T-cell activation.

Clinical Applications

• Organ transplantation: Prevention of rejection (kidney, liver, heart)
• Autoimmune diseases: Rheumatoid arthritis, psoriasis, atopic dermatitis
• Uveitis: Sight-threatening posterior uveitis
• Nephrotic syndrome: Steroid-resistant minimal change disease

Pharmacokinetics

• Half-life: 6-12 hours
• Tmax: 1.5-2 hours (Neoral), 3-4 hours (Sandimmune)
• Bioavailability: 20-50% (variable with formulation)
• Metabolism: CYP3A4 liver metabolism
• Distribution: High volume of distribution, extensive tissue binding

Safety and Side Effects

Nephrotoxicity (most significant, dose-dependent), hypertension, hyperlipidemia, diabetes mellitus, gingival hyperplasia, hirsutism, hepatotoxicity, and increased infection/malignancy risk. Narrow therapeutic index requires TDM.

References

• Borel, J.F., et al. (1976). Cyclosporine A: a new antilymphocytic agent. Agents and Actions, 6, 468-475.
• Kahan, B.D. (1989). Cyclosporine. New England Journal of Medicine, 321, 1725-1738.