General
Preferred name
CYCLOSPORINE
Synonyms
Cyclosporine A ()
ciclosporin ()
cyclosporin A ()
Ciclosporin A ()
CsA ()
Ciclosporin ()
Zinograf me ()
27-400 ()
Verkazia ()
Optimmune ()
Restasis multidose ()
Mitogard ()
Vanquoral ()
Ciclosporina ()
Ciclosporinum ()
Vevye ()
ANTIBIOTIC S-7481F1 ()
Gengraf ()
Neurostat ()
Capimune ()
Cyclosporin A ()
OL-27-400 ()
SDZ-OXL-400 ()
Cequa ()
Sandimmune ()
Sangcya ()
Restasis ()
Atopica ()
Sandimmun ()
Ciclosporine ()
Ramihyphin a ()
Capsorin ()
Neoplanta ()
Cyclosporine microemulsion ()
Neoral ()
SANG-35 ()
Cyclosporin ()
Cyclosporine, modified ()
Equoral ()
Deximune ()
NSC-290193 ()
Ikervis ()
P&D ID
PD013140
CAS
59865-13-3
55126-45-9
104250-72-8
Tags
available
PROTAC
drug
Approved by
EMA
PMDA
FDA
First approval
1983
Drug Status
vet_approved
approved
investigational
Max Phase
4.0
Drug indication
atopic eczema
Structure
Probe scores
P&D probe-likeness score
[[ v.score ]]%
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
PHARMACODYNAMICS As the major mechanism of action, cyclosporine has been shown to suppress T cells and T cell cytokine production.[A174052] The secondary mechanisms are known to inhibit the growth and activation of B cells[A174055] and antigen presenting cells[A174058], reduce the production of antibodies[A174061], the degranulation, histamine release, leukotriene synthesis[A174067] and expression of adhesion molecule.[A174064] Cyclosporine has shown efficacy in induced animal models of conditions that are proven to have an immune component. The range of tested conditions goes from asthma to multiple sclerosis. However, in most of these models, the recurrence of the condition after treatment discontinuation is a very common feature. Cyclosporine showed a good profile in the prophylaxis and treatment of keratoconjunctivitis and arthritis as well as a prophylactic agent in vitiligo and diabetes mellitus.[A174088] Cyclosporine has been attributed to some vasoconstrictor activities which provide a potential to cause hypertension and renal dysfunction. In the kidneys, it has been shown to affect the proximal tubule and afferent arteriole indicating the potential of nephrotoxicity.[A174088]
INDICATION Cyclosporine is officially approved for different conditions listed below: * Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. For this indication, it can be used concomitantly with azathioprine and corticosteroids. * Treatment of patients with severe active, rheumatoid arthritis when the patient no longer responds to methotrexate. * Concomitantly with methotrexate for the treatment of patients with severe active rheumatoid arthritis when patients do not respond to methotrexate treatment alone. * Treatment of adult nonimmunocompromised patients with severe, recalcitrant, plaque psoriasis that have failed to respond to at least one systemic therapy or when systemic therapies are not tolerated or contraindicated.[FDA label] * Its ophthalmic solution is indicated to increase tear production in patients with keratoconjunctivitis sicca in patients from 4 years old.[L5158] * Prevention of graft rejection following bone marrow transplantation and in the treatment of graft-versus-host disease (GVHD). * Treatment of steroid dependent and steroid-resistant nephrotic syndrome due to glomerular diseases such as minimal change nephropathy, focal and segmental glomerulosclerosis or membranous glomerulonephritis in adults and children.[F3091] Away from all this approved and reviewed indications, cyclosporine is commonly used on dermatology for the treatment of various inflammatory skin conditions such as atopic dermatitis, blistering disorders, and connective tissue diseases.[A174085]
ROE It is thought that after cyclosporine sulfate conjugation as part of the metabolic pathway, this compound can remain in the bile where it is degraded to the original compound and re-absorbed. The elimination profile is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in the urine while 90% of the administered dose is eliminated in the bile. Form the excreted proportion, less than 1% of the dose is excreted as unchanged drug.[A174088]
TOXICITY The oral LD50 of cyclosporine in mice is 2329 mg/kg. In cases of overdose, forced emesis and gastric lavage are recommended 2 hours after administration. After the intervention, transient hepatotoxicity and nephrotoxicity are still observed. However, doses of up to 150 mg/kg are tolerated with minor clinical consequences. Serious intoxication has been reported in accidental overdosage in premature neonates. When overdose with cyclosporine is observed, it is important to consider that dialysis and charcoal hemoperfusion are not responsive techniques.[FDA label] Cyclosporine was shown to present a trend for the generation of lymphocytic lymphomas, pancreatic islet carcinomas and hepatocellular carcinomas. It was not shown to present mutagenic or genotoxic potential and to not have any effect on fertility.[FDA label]
METABOLISM Cyclosporine is metabolized in the intestine and the liver by the action of the CYP450 isoenzyme group.[A174049] There is no single major metabolic pathway and from cyclosporine metabolism, there have been observed over 30 different metabolites. The most active metabolite shows only 10-20% activity when compared to the parent compound and they do not act synergistically.[A174088] The major metabolites (M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively.[FDA label]
ABSORPTION The absorption of cyclosporine is known to be done mainly in the small intestine.[A174049] The latest formulation of cyclosporine presented a bioavailability, AUC and Cmax higher than the original oily formulation.[A174076] However, the absorption is very limited and presents only a bioavailability of 30% and the peak concentration is observed after 1-8 hours of initial administration with a second peak observed in some patients. The presence of a second peak is thought to be due to enhanced absorption due to concomitant food administration as bile can increase cyclosporine absorption.[A174088]
HALF-LIFE The half-life of cyclosporine is biphasic and very variable on different conditions but it is reported in general to be of 19 hours.[A174088]
PHARMACODYNAMICS As the major mechanism of action, cyclosporine has been shown to suppress T cells and T cell cytokine production.[A174052] The secondary mechanisms are known to inhibit the growth and activation of B cells[A174055] and antigen presenting cells[A174058], reduce the production of antibodies[A174061], the degranulation, histamine release, leukotriene synthesis[A174067] and expression of adhesion molecule.[A174064]; ; Cyclosporine has shown efficacy in induced animal models of conditions that are proven to have an immune component. The range of tested conditions goes from asthma to multiple sclerosis. However, in most of these models, the recurrence of the condition after treatment discontinuation is a very common feature. Cyclosporine showed a good profile in the prophylaxis and treatment of keratoconjunctivitis and arthritis as well as a prophylactic agent in vitiligo and diabetes mellitus.[A174088]; ; Cyclosporine has been attributed to some vasoconstrictor activities which provide a potential to cause hypertension and renal dysfunction. In the kidneys, it has been shown to affect the proximal tubule and afferent arteriole indicating the potential of nephrotoxicity.[A174088]
MOA In a nutshell, cyclosporine is a calcineurin inhibitor and this activity allows for inhibition of T cell activation.[A174049]; ; Cyclosporine's pharmacological action is obtained by the binding to the intracellular receptor cyclophilin-1 which produces the complex ciclosporin-cyclophilin. This complex will in order inhibit calcineurin which will prevent the dephosphorylation and activation of the nuclear factor of activated T cells (NF-AT). The NF-AT is a transcription factor that regulates the production of pro-inflammatory cytokines such as IL-2, IL-4, interferon-gamma and TNF-alpha.[A174049]; ; The critical role of this inhibition cascade relies on the specific inhibition of IL-2 due to the major role of this interleukin on the activation and proliferation of T cells. On the second plane, the inhibition of NF-AT also produces a deficiency of other factors related to T helper cell differentiation, T cell tolerance, and thymocyte development. Some reports even indicate a role of NF-AT on innate immunity giving cyclosporine a regulatory activity on both innate and adaptative immune responses.[A174049]
INDICATION Cyclosporine is officially approved for different conditions listed below:; ; * Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. For this indication, it can be used concomitantly with azathioprine and corticosteroids.; ; * Treatment of patients with severe active, rheumatoid arthritis when the patient no longer responds to methotrexate. ; ; * Concomitantly with methotrexate for the treatment of patients with severe active rheumatoid arthritis when patients do not respond to methotrexate treatment alone.; ; * Treatment of adult nonimmunocompromised patients with severe, recalcitrant, plaque psoriasis that have failed to respond to at least one systemic therapy or when systemic therapies are not tolerated or contraindicated.[FDA label]; ; * Its ophthalmic solution is indicated to increase tear production in patients with keratoconjunctivitis sicca in patients from 4 years old.[L5158]; ; * Prevention of graft rejection following bone marrow transplantation and in the treatment of graft-versus-host disease (GVHD).; ; * Treatment of steroid dependent and steroid-resistant nephrotic syndrome due to glomerular diseases such as minimal change nephropathy, focal and segmental glomerulosclerosis or membranous glomerulonephritis in adults and children.[F3091]; ; Away from all this approved and reviewed indications, cyclosporine is commonly used on dermatology for the treatment of various inflammatory skin conditions such as atopic dermatitis, blistering disorders, and connective tissue diseases.[A174085]
TOXICITY The oral LD50 of cyclosporine in mice is 2329 mg/kg. In cases of overdose, forced emesis and gastric lavage are recommended 2 hours after administration. After the intervention, transient hepatotoxicity and nephrotoxicity are still observed. However, doses of up to 150 mg/kg are tolerated with minor clinical consequences. Serious intoxication has been reported in accidental overdosage in premature neonates. When overdose with cyclosporine is observed, it is important to consider that dialysis and charcoal hemoperfusion are not responsive techniques.[FDA label]; ; Cyclosporine was shown to present a trend for the generation of lymphocytic lymphomas, pancreatic islet carcinomas and hepatocellular carcinomas. It was not shown to present mutagenic or genotoxic potential and to not have any effect on fertility.[FDA label]
METABOLISM Cyclosporine is metabolized in the intestine and the liver by the action of the CYP450 isoenzyme group.[A174049] There is no single major metabolic pathway and from cyclosporine metabolism, there have been observed over 30 different metabolites. The most active metabolite shows only 10-20% activity when compared to the parent compound and they do not act synergistically.[A174088]; ; The major metabolites (M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively.[FDA label]
ABSORPTION The absorption of cyclosporine is known to be done mainly in the small intestine.[A174049] The latest formulation of cyclosporine presented a bioavailability, AUC and Cmax higher than the original oily formulation.[A174076] However, the absorption is very limited and presents only a bioavailability of 30% and the peak concentration is observed after 1-8 hours of initial administration with a second peak observed in some patients. The presence of a second peak is thought to be due to enhanced absorption due to concomitant food administration as bile can increase cyclosporine absorption.[A174088]; ;
DESCRIPTION Originally isolated from Tolypocladium inflatum, cyclosporin A acts as a calcineurin inhibitor.
There is some ambiguity in the literature as to the exact stereochemistry of cyclosporin A. Other common representations on PubChem are CID 5280754, and CID 24883466. (GtoPdb)
MOA In a nutshell, cyclosporine is a calcineurin inhibitor and this activity allows for inhibition of T cell activation.[A174049] Cyclosporine's pharmacological action is obtained by the binding to the intracellular receptor cyclophilin-1 which produces the complex ciclosporin-cyclophilin. This complex will in order inhibit calcineurin which will prevent the dephosphorylation and activation of the nuclear factor of activated T cells (NF-AT). The NF-AT is a transcription factor that regulates the production of pro-inflammatory cytokines such as IL-2, IL-4, interferon-gamma and TNF-alpha.[A174049] The critical role of this inhibition cascade relies on the specific inhibition of IL-2 due to the major role of this interleukin on the activation and proliferation of T cells. On the second plane, the inhibition of NF-AT also produces a deficiency of other factors related to T helper cell differentiation, T cell tolerance, and thymocyte development. Some reports even indicate a role of NF-AT on innate immunity giving cyclosporine a regulatory activity on both innate and adaptative immune responses.[A174049]
DESCRIPTION Cyclosporin A (Cyclosporine A) is an immunosuppressant which binds to the cyclophilin and inhibits phosphatase activity of protein phosphatase 2B (PP2B/calcineurin) with an IC50 of 5 nM[3]. Cyclosporin A also inhibits CD11a/CD18 adhesion[8].
DESCRIPTION Cytochrome P450c17 inhibitor (Tocris Bioactive Compound Library)
DESCRIPTION Cyclosporine is a steroid-sparing immunosuppressant used in organ and bone marrow transplants as well as inflammatory conditions such as ulcerative colitis, rheumatoid arthritis, and atopic dermatitis. (Enamine Bioactive Compounds)
DESCRIPTION Cyclosporin A is a naturally occurring cyclic polypeptide that is the active metabolite of a fungus. Cyclosporin A is an immunosuppressant that binds to procyclins and inhibits calcineurin (IC50=7 nM). (TargetMol Bioactive Compound Library)
Cell lines
17
Organisms
18
Compound Sets
20
AdooQ Bioactive Compound Library
A10260
Cayman Chemical Bioactives
12088
ChEMBL Approved Drugs
CHEMBL160
ChEMBL Drugs
CHEMBL160
CZ-OPENSCREEN Bioactive Library
DrugBank
DB00091
DrugBank Approved Drugs
DB00091
DrugCentral
760
DrugCentral Approved Drugs
760
Enamine Bioactive Compounds
EBC-27538
Guide to Pharmacology
1024
JUMP-Target 1 Compound Set
5284373
LSP-MoA library (Laboratory of Systems Pharmacology)
CHEMBL160
MedChem Express Bioactive Compound Library
HY-B0579
NCATS Inxight Approved Drugs
83HN0GTJ6D
Novartis Chemogenetic Library (NIBR MoA Box)
Prestwick Chemical Library
ReFrame library
TargetMol Bioactive Compound Library
T0945
Tocris Bioactive Compound Library
1101
External IDs
58
Properties
(calculated by RDKit )
Molecular Weight
1201.84
Hydrogen Bond Acceptors
12
Hydrogen Bond Donors
5
Rotatable Bonds
15
Ring Count
1
Aromatic Ring Count
0
cLogP
3.27
TPSA
278.8
Fraction CSP3
0.79
Chiral centers
12.0
Largest ring
33.0
QED
0.15
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Pathway
Immunology/Inflammation
Metabolism
Microbiology/virology
Anti-infection
Primary Target
Protein Ser/Thr Phosphatases
MOA
Inhibitor
binds to cyclophilin
calcineurin inhibitor
Cyclophilin modulator
Cyclophilin D Inhibitors
Cyclphilin A Inhibitors
Member status
member
Target
FPR1
antibiotic
Complement System
Cyclophilin
Molecular Glues
calcineurin phosphatase
phosphatase
Source data