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Systematic (IUPAC) name
Clinical data
Trade names Neoral, Sandimmune
AHFS/ monograph
MedlinePlus a601207
Pregnancy cat. C (AU) C (US)
Routes Oral, IV, ophthalmic
Pharmacokinetic data
Bioavailability Variable
Metabolism Hepatic CYP3A4
Half-life Variable (about 24 hours)
Excretion Biliary
CAS number 59865-13-3 YesY
ATC code L04AD01 S01XA18
PubChem CID 5284373
DrugBank DB00091
ChemSpider 4447449 YesY
KEGG D00184 YesY
Chemical data
Formula C62H111N11O12 
Mol. mass 1202.61 g/mol
 N (what is this?)  (verify)

Ciclosporin (INN/BAN) (pronounced /ˌskləˈspɔrɪn/);[1] cyclosporine (USAN); cyclosporin (former BAN); or ciclosporin A,[citation needed] cyclosporine A, or cyclosporin A (often shortened to CsA) is an immunosuppressant drug widely used in organ transplantation to prevent rejection. It reduces the activity of the immune system by interfering with the activity and growth of T cells.[2][3] It was initially isolated from the fungus Tolypocladium inflatum (Beauveria nivea), found in a soil sample obtained in 1969 from Hardangervidda, Norway, by Hans Peter Frey, a Sandoz biologist.[4] Most peptides are synthesized by ribosomes, but ciclosporin is a cyclic nonribosomal peptide of 11 amino acids and contains a single D-amino acid, which are rarely encountered in nature.[5]


The immunosuppressive effect of ciclosporin was discovered on 31 January 1972 by employees of Sandoz (now Novartis) in Basel, Switzerland, in a screening test on immune suppression designed and implemented by Hartmann F. Stähelin. The success of ciclosporin in preventing organ rejection was shown in kidney transplants by R.Y. Calne and colleagues at the University of Cambridge,[6] and in liver transplants performed by Thomas Starzl at the University of Pittsburgh Hospital. The first patient, on 9 March 1980, was a 28-year-old woman.[7] Ciclosporin was subsequently approved for use in 1983.

Medical uses[edit]

Ciclosporin is approved by the FDA to prevent and treat graft-versus-host disease in bone-marrow transplantation and to prevent rejection of kidney, heart, and liver transplants.[8][9] It is also approved in the US for the treatment of rheumatoid arthritis and psoriasis[9] and as an ophthalmic emulsion for the treatment of dry eyes.[10]

In addition to these indications, ciclosporin is also used in severe atopic dermatitis, Kimura's disease, pyoderma gangrenosum, chronic autoimmune urticaria, and, infrequently, in rheumatoid arthritis and related diseases, although it is only used in severe cases.

Ciclosporin has also been used to help treat patients with acute severe ulcerative colitis that do not respond to treatment with steroids.[11] This drug is also used as a treatment of posterior or intermediate uveitis with noninfective etiology.[citation needed]

It is sometimes prescribed in veterinary cases, particularly in extreme cases of immune-mediated hemolytic anemia.[12]

Adverse effects[edit]


ADRs can include gingival hyperplasia, convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion, hypercholesterolemia, dyspnea, numbness and tingling particularly of the lips, pruritus, high blood pressure, potassium retention possibly leading to hyperkalemia, kidney and liver dysfunction (nephrotoxicity[13] and hepatotoxicity), burning sensations at finger tips and an increased vulnerability to opportunistic fungal and viral infections.In short, it is nephrotoxic, neurotoxic, causes hypertension (due to renal vasoconstriction and increased sodium reabsorption), increases the risk of squamous cell carcinoma and infections. It also causes gingival hypertrophy and hirsutism which is not seen with tacrolimus (another calcineurin inhibitor).

An alternate form of the drug, cyclosporin G (OG37-324), has been found to be much less nephrotoxic than the standard ciclosporin (cyclosporin A).[14] Cyclosporin G (molecular mass 1217) differs from cyclosporin A in the amino acid 2 position, where an L-norvaline replaces the α-aminobutyric acid.[15]

OPM superfamily 174
OPM protein 1cwa

Ciclosporin is listed as IARC Group 1 carcinogens (sufficient evidence of carcinogenicity in humans).

Mechanism of action[edit]

In medicine, the most important effect of ciclosporin is to lower the activity of T cells and their immune response.


Ciclosporin affects mitochondria by preventing the mitochondrial permeability transition pore from opening, thus inhibiting cytochrome c release, a potent apoptotic stimulation factor. This is not the primary mechanism of action for clinical use, but is an important effect for research on apoptosis.

Ciclosporin binds to the cyclophilin D protein (CypD) that constitutes part of the mitochondrial permeability transition pore (MPTP),[17][18] and by inhibiting the calcineurin phosphatase pathway.[17][19][20] The MPTP is found in the mitochondrial membrane of cardiac myocytes (heart muscle cells) and moves calcium ions (Ca2+
) into the mitochondria.[17][18] When open, Ca2+
enters the mitochondria, disrupting transmembrane potential (the electric charge across a membrane). If unregulated, this can contribute to mitochondrial swelling and dysfunction.[18] To allow for normal contraction, intracellular Ca2+
increases, and the MPTP in turn opens, shuttling Ca2+
into the mitochondria.[18] Calcineurin is a Ca2+
-activated phosphatase (enzyme that removes a phosphate group from substrate) that regulates cardiac hypertrophy.[21][19][22] Regulation occurs through NFAT (nuclear factor of activated T-cells) activation, which, when dephosphorylated, binds to GATA and forms a transcription factor (protein that can bind DNA and alter the expression of DNA) with ability to control the hypertrophic gene (2). Activation of calcineurin causes increases in hypertrophy.[21][19]

Metabolism and metabolite activity[edit]

Ciclosporin is highly metabolized in humans and animals after ingestion. The resulting metabolites include cyclosporin B, C, D, E, H, L, and others.[23] Ciclosporin metabolites have been found to have lower immunosuppressant activity than CsA (approximately <10%), and are associated with higher nephrotoxicity.[24] Individual ciclosporin metabolites have been isolated and characterized but do not appear to be extensively studied.




Figure 2: Butenyl-methyl-L-threonine biosynthesis







Ciclosporin has been investigated as a possible neuroprotective agent in conditions such as traumatic brain injury, and has been shown in animal experiments to reduce brain damage associated with injury.[33] Ciclosporin blocks the formation of the mitochondrial permeability transition pore, which has been found to cause much of the damage associated with head injury and neurodegenerative diseases. Ciclosporin's neuroprotective properties were first discovered in the early 1990s when two researchers (Eskil Elmér and Hiroyuki Uchino) were conducting experiments in cell transplantation. An unintended finding was that CsA was strongly neuroprotective when it crossed the blood–brain barrier.[34] This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.[35]

Cardiac disease[edit]

Ciclosporin has been used experimentally treat cardiac hypertrophy[17][21] (an increase in cell volume).

Inappropriate opening of the mitochondrial permeability transition pore (MPTP) manifests in ischemia[17] (blood flow restriction to tissue) and reperfusion injury[17] (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction[19] (heart attack) and when mutations in mitochondrial DNA polymerase occur.[17] The heart attempts to compensate for disease state by increasing the intracellular Ca2+
to increase the contractility cycling rates.[18] Constitutively high levels of mitochondrial Ca2+
cause inappropriate MPTP opening leading to a decrease in the cardiac range of function, leading to cardiac hypertrophy as an attempt to compensate for the problem.[19][18]

CsA has been shown to decrease cardiac hypertrophy by affecting cardiac myocytes in many ways. CsA binds to cyclophilin D to block the opening of MPTP, and thus decreases the release of protein cytochrome C, which can cause programmed cell death.[17][18][36] CypD is a protein within the MPTP that acts as a gate; binding by CsA decreases the amount of inappropriate opening of MPTP, which decreases the intramitochondrial Ca2+
.[18] Decreasing intramitochondrial Ca2+
allows for reversal of cardiac hypertrophy caused in the original cardiac response.[18] Decreasing the release of cytochrome C caused decreased cell death during injury and disease.[17] CsA also inhibits the phosphatase calcineurin pathway (14).[17][19][22] Inhibition of this pathway has been shown to decrease myocardial hypertrophy.[21][19][22]

See also[edit]


  1. ^ "cyclosporin". Unabridged. Random House. [n.d.] Retrieved 2011-07-13. 
  2. ^ Henry J. Kaminski (26 November 2008). Myasthenia Gravis and Related Disorders. Springer. p. 163. "Cyclosporine is derived from a fungus and is a cyclic undecapeptide with actions directed exclusively on T cells." 
  6. ^ Calne RY, White DJG, Thiru S, Evans DB, McMaster P, Dunn DC, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. The Lancet 1978/II:1323-1327
  8. ^ [ SandImmune Label
  9. ^ a b Neoral Label
  10. ^ Restasis Label
  12. ^ Palmeiro BS. Cyclosporine in veterinary dermatology. Vet Clin North Am Small Anim Pract. 2013 Jan;43(1):153-71. PMID 23182330
  26. ^ Hoppert M, Gentzsch C, Schörgendorfer K (October 2001). "Structure and localization of cyclosporin synthetase, the key enzyme of cyclosporin biosynthesis in Tolypocladium inflatum". Arch. Microbiol. 176 (4): 285–93. doi:10.1007/s002030100324. PMID 11685373. 
  28. ^ Sandimmune Prescribing Information
  29. ^ Gibaud, S. P.; Attivi, D. (2012). "Microemulsions for oral administration and their therapeutic applications". Expert Opinion on Drug Delivery: 1. doi:10.1517/17425247.2012.694865.  edit
  30. ^ Neoral Prescribing Information
  31. ^

External links[edit]