Cyclosporin A
From ToxBankWiki
Cyclosporin A | |
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Identifiers | |
Leadscope Id | LS-257 |
CAS | 59865-13-3 |
DrugBank | DB00091 |
ChemSpider | 4447449 |
UNII | 83HN0GTJ6D |
ChEBI | 15377 |
Pathway DBs | |
KEGG | D00184 |
Assay DBs | |
PubChem CID | 5284373 |
ChEMBL | 160 |
Omics DBs | |
Properties | |
pKa | 9.45 |
ToxCast Accepted | no |
Toxic Effect | Cholestasis |
ToxBank Accepted | no |
Target | cyclophilin |
Executive Summary
Compound | Cyclosporin A |
Toxicities | Cholestasis, renal fibrosis |
Mechanisms | Not known. |
Comments | Cyclosporin A is a large natural product with multiple functional groups that may potentially relate to toxicity. We found no clear description of the mechanism of hepatotoxicity. The chemical structure and pharmacological mechanism of action are relatively unique, which means that it may be difficult to generalize results to other compounds or to identify controls for ‘omics experiments. In addition, the compound binds to glass and plastic, making handling difficult. These features argue against cyclosporine A as a standard. |
Recommended as Standard | No |
Summary Information
The table listed below contains a summarized listing of toxic effect information leveraged from the 6th European Framework Programme project LIINTOP. For a complete listing of the Gold Compound evaluation criteria please see the Gold Compound Evaluation and Comments immediately following the summary table below.
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Summary Hepatotoxic Effects from the LIINTOP FP6 Program | |||||||||||||||||||||||
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+ | + | 3 |
[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] |
Gold Compound Evaluation and Comments
The following table is organized into four main sections and provides a detailed assessment by the Gold Compound Working Group for the use of this compound as a standard hepatotoxin. The table's four sections (collapsed by default but will expand when the "show" link is clicked) contains detailed information for the core set of SEURAT compound acceptance criteria.
Standard to Meet | Compound Assessment | ||||||||||||||||||
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Proprietary Toxicity Literature Report
The toxicity literature report contains proprietary information and references for studies performed on this compound relevant to liver toxicity findings and is restricted for use within the SEURAT program only.
Human Adverse Events
The following data table has been mined from the Adverse Events Reporting System (AERS) of the US FDA. Significant human liver events. The first column ("# Reports") is the number of reports found for the corresponding adverse event reported in the third column ("Adverse Event"). The second column ("Report:Baseline Ratio") is ratio calculated from the number of reports ("# Reports") divided by a calculated expected statistical baseline number of reports.
# Reports | Report:Baseline Ratio | Adverse Event |
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11 | 10.327 | acute graft versus host disease in liver |
4 | 4.39262 | adenoviral hepatitis |
1 | 26.5997 | bacillary angiomatosis |
12 | 3.37576 | bile duct stenosis |
10 | 17.7332 | biliary anastomosis complication |
9 | 3.25465 | biliary dilatation |
6 | 15.9598 | biliary ischaemia |
2 | 7.1462 | biliary sepsis |
6 | 42.2467 | cholangitis chronic |
10 | 3.28843 | cholecystitis chronic |
2 | 4.83632 | cholestasis of pregnancy |
13 | 6.51082 | complications of transplanted liver |
1 | 10.8817 | congenital absence of bile ducts |
9 | 12.0368 | cytomegalovirus hepatitis |
1 | 26.5997 | dilatation intrahepatic duct congenital |
7 | 5.62344 | gallbladder enlargement |
2 | 4.39262 | gallbladder non-functioning |
2 | 5.83897 | haemobilia |
3 | 4.46083 | hepatic artery aneurysm |
4 | 16.5102 | hepatic artery occlusion |
14 | 5.48538 | hepatic artery thrombosis |
6 | 7.18193 | hepatic cancer metastatic |
3 | 47.8795 | hepatic cyst infection |
4 | 23.9398 | hepatic neoplasm malignant non-resectable |
9 | 21.3325 | hepatic neoplasm malignant recurrent |
5 | 8.19855 | hepatic vein occlusion |
1 | 47.8795 | hepatitis g |
1 | 14.9624 | hepatitis infectious mononucleosis |
9 | 3.56718 | hepatitis viral |
1 | 9.57591 | hepatoblastoma |
9 | 3.66425 | hepatorenal failure |
1 | 11.3999 | hyperphosphatasaemia |
1 | 8.54992 | leukaemic infiltration hepatic |
15 | 3.35604 | liver abscess |
107 | 12.6061 | liver transplant rejection |
2 | 3.65493 | nodular regenerative hyperplasia |
1 | 12.5999 | oedema due to hepatic disease |
7 | 9.85755 | peliosis hepatis |
5 | 29.9247 | portal vein occlusion |
4 | 25.8808 | portal vein stenosis |
42 | 6.98728 | venoocclusive liver disease |
FDA and Label Information
The following link will display all of the currently approved FDA drug products on the market. The web page will contain a table listing all current products by their respective Tradenames and primary active ingredients. The list is navigable by simply clicking on the product of interest, which will in turn list all of the NDA's and ANDA's associated with that product. From here users can click on a specific NDA or ANDA and see documents that have been submitted for the product that the FDA has made available via their website. The types of documents include approval history, letters, reviews and labels.
FDA Approved Products
This next url will perform a search in the FDA's system for all labels for products that contain "Cyclosporin A" as an active ingredient.
FDA Label Search
PubMed references
The following resource link will perform a PubMed query for the terms "Cyclosporin A" and "liver toxicity".
Cyclosporin A Search
References
- ↑ Cullen, J.M., 2005. Mechanistic classification of liver injury. Toxicol. Pathol. 33, 6–8.
- ↑ Geier, A., Dietrich, C.G., Gerloff, T., Haendly, J., Kullak-Ublick, G.A., Stieger, B., Meier, P.J., Matern, S., Gartung, C., 2003. Regulation of basolateral organic anion transporters in ethinylestradiol-induced cholestasis in the rat. Biochim. Biophys. Acta 1609, 87–94.
- ↑ Loranger, A., Barriault, C., Yousef, I.M., Tuchweber, B., 1996. Structural and functional alterations of hepatocytes during transient phalloidin-induced cholestasis in the rat. Toxicol. Appl. Pharmacol. 137, 100–111.
- ↑ Pauli-Magnus, C., Meier, P.J., 2006. Hepatobiliary transporters and drug-induced cholestasis. Hepatology 44, 778–787.
- ↑ Rolo, A.P., Oliveira, P.J., Seica, R., Santos, M.S., Moreno, A.J., Palmeira, C.M., 2002. Disruption of mitochondrial calcium homeostasis after chronic alphanaphthylisothiocyanate administration: relevance for cholestasis. J. Invest. Med. 50, 193–200.
- ↑ Roman, I.D., Fernandez-Moreno, M.D., Fueyo, J.A., Roma, M.G., Coleman, R., 2003. Cyclosporin A induced internalization of the bile salt export pump in isolated rat hepatocyte couplets. Toxicol. Sci. 71, 276–281.
- ↑ Sokol, R.J., Dahl, R., Devereaux, M.W., Yerushalmi, B., Kobak, G.E., Gumpricht, E., 2005. Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids. J. Pediatr. Gastroenterol. Nutr. 41, 235–243.
- ↑ Thibault, N., Claude, J.R., Ballet, F., 1992. Actin filament alteration as a potential marker for cholestasis: a study in isolated rat hepatocyte couplets. Toxicology 73, 269–279.
- ↑ Zollner, G., Trauner, M., 2008. Mechanisms of cholestasis. Clin. Liver Dis. 12, 1–26 (vii).
- ↑ Geier, A., Dietrich, C.G., Gerloff, T., Haendly, J., Kullak-Ublick, G.A., Stieger, B., Meier, P.J., Matern, S., Gartung, C., 2003. Regulation of basolateral organic anion transporters in ethinylestradiol-induced cholestasis in the rat. Biochim. Biophys. Acta 1609, 87–94.
- ↑ Loranger, A., Barriault, C., Yousef, I.M., Tuchweber, B., 1996. Structural and functional alterations of hepatocytes during transient phalloidin-induced cholestasis in the rat. Toxicol. Appl. Pharmacol. 137, 100–111.
- ↑ Marion, T.L., Leslie, E.M., Brouwer, K.L., 2007. Use of sandwich-cultured hepatocytes to evaluate impaired bile acid transport as a mechanism of drug-induced hepatotoxicity. Mol. Pharm. 4, 911–918.
- ↑ Palmeira, C.M., Rolo, A.P., 2004. Mitochondrially-mediated toxicity of bile acids. Toxicology 203, 1–15.
- ↑ Pauli-Magnus, C., Meier, P.J., 2006. Hepatobiliary transporters and drug-induced cholestasis. Hepatology 44, 778–787.
- ↑ Rolo, A.P., Oliveira, P.J., Seica, R., Santos, M.S., Moreno, A.J., Palmeira, C.M., 2002. Disruption of mitochondrial calcium homeostasis after chronic alphanaphthylisothiocyanate administration: relevance for cholestasis. J. Invest. Med. 50, 193–200.
- ↑ Roman, I.D., Fernandez-Moreno, M.D., Fueyo, J.A., Roma, M.G., Coleman, R., 2003. Cyclosporin A induced internalization of the bile salt export pump in isolated rat hepatocyte couplets. Toxicol. Sci. 71, 276–281.
- ↑ Sokol, R.J., Dahl, R., Devereaux, M.W., Yerushalmi, B., Kobak, G.E., Gumpricht, E., 2005. Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids. J. Pediatr. Gastroenterol. Nutr. 41, 235–243.
- ↑ Thibault, N., Claude, J.R., Ballet, F., 1992. Actin filament alteration as a potential marker for cholestasis: a study in isolated rat hepatocyte couplets. Toxicology 73, 269–279.
- ↑ Zollner, G., Trauner, M., 2008. Mechanisms of cholestasis. Clin. Liver Dis. 12, 1–26 (vii).
- ↑ Criddle, D.N., Gillies, S., Baumgartner-Wilson, H.K., Jaffar, M., Chinje, E.C., Passmore, S., Chvanov, M., Barrow, S., Gerasimenko, O.V., Tepikin, A.V., Sutton, R., Petersen, O.H., 2006. Menadione-induced reactive oxygen species generation via redox cycling promotes apoptosis of murine pancreatic acinar cells. J. Biol. Chem. 281, 40485–40492.
- ↑ Hanley, P.J., Ray, J., Brandt, U., Daut, J., 2002. Halothane, isoflurane and sevoflurane inhibit NADH:ubiquinone oxidoreductase (complex I) of cardiac mitochondria. J. Physiol. 544, 687–693.
- ↑ Moridani, M.Y., Cheon, S.S., Khan, S., O’Brien, P.J., 2003. Metabolic activation of 3- hydroxyanisole by isolated rat hepatocytes. Chem. Biol. Interact. 142, 317–333.
- ↑ Pereira, C.V., Moreira, A.C., Pereira, S.P., Machado, N.G., Carvalho, F.S., Sardao, V.A., Oliveira, P.J., 2009. Investigating drug-induced mitochondrial toxicity: a biosensor to increase drug safety? Curr. Drug Saf. 4, 34–54.
- ↑ Sanz, A., Caro, P., Gomez, J., Barja, G., 2006. Testing the vicious cycle theory of mitochondrial ROS production: effects of H2O2 and cumene hydroperoxide treatment on heart mitochondria. J. Bioenerg. Biomembr. 38, 121–127.
- ↑ Yuan, L., Kaplowitz, N., 2009. Glutathione in liver diseases and hepatotoxicity. Mol. Aspects Med. 30, 29–41.
- ↑ Toxicity should be observed clinically with higher frequency at higher doses. If toxicity is idiosyncratic due to defects in metabolism that result in higher than normal exposure, then this toxicity is still considered to fit our definition of dose-dependent toxicity. If toxicity is idiosyncratic due to an increased sensitivity of the organ to the toxin - due to disease, genetics, or co-administered drug, for example - then this toxicity is outside our area of interest.
- ↑ The in vivo therapeutic window is used to estimate an appropriate concentration for in vitro toxicity assays. This in vitro concentration should also be consistent with the exposure implied by pharmacokinetics parameters.
- ↑ 28.0 28.1 We prefer compounds that require metabolic activation, although standards that are active in themselves will be accepted if they have otherwise valuable properties. We require knowing the active metabolite, and we prefer compounds where the metabolite is stable and can be independently tested in order to verify the mechanism of toxicity as well as of metabolic activation in the test cell line.
- ↑ Literature data for at least one, but not necessarily all, of the ‘omics datasets is desired. This requirement can be waived in special cases.
- ↑ 30.0 30.1 30.2 30.3 30.4 The IC50’s for in vitro efficacy and toxicity should be consistent with the therapeutic ratio observed in the clinic. These parameters will be dependent on specific cell type and culture conditions, but differences of more than 30-fold in the in vitro vs. in vivo therapeutic ratios should be considered suspect and carefully justified.
- ↑ This is not a equirement, but compounds utilized in the EPA testing program can be assumed to have physical properties verified to be suitable for in vitro cellular assays.
- ↑ Sparing soluble compounds may be assayed for solubility in serum and the percent serum used specified here.
- ↑ This property will be measured when a sample of compound becomes available.
Calculated/Predicted Properties
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Accepted by ToxBank | no + |
Accepted by ToxCast | no + |
Equivalent URIThis property is a special property in this wiki. | http://bio2rdf.org/drugbank_drugs:DB00091 +, http://bio2rdf.org/cas:59865-13-3 +, http://www.chemspider.com/Chemical-Structure.4447449.rdf +, http://bio2rdf.org/pubchem:5284373 +, http://bio2rdf.org/dr:D00184 +, http://bio2rdf.org/chebi:15377 +, and http://rdf.openmolecules.net/?InChI=1S/C62H111N11O12/c1-25-27-28-40(15)52(75)51-56(79)65-43(26-2)58(81)67(18)33-48(74)68(19)44(29-34(3)4)55(78)66-49(38(11)12)61(84)69(20)45(30-35(5)6)54(77)63-41(16)53(76)64-42(17)57(80)70(21)46(31-36(7)8)59(82)71(22)47(32-37(9)10)60(83)72(23)50(39(13)14)62(85)73(51)24/h25,27,34-47,49-52,75H,26,28-33H2,1-24H3,(H,63,77)(H,64,76)(H,65,79)(H,66,78) + |
Has CAS | 59865-13-3 + |
Has ChEBI Id | 15377 + |
Has ChEMBL Id | 160 + |
Has ChemSpider Id | 4447449 + |
Has DrugBank Id | DB00091 + |
Has InChI | warning.pngString representation InChI=1S/C62H111N11O12/c1-25-27-28-40(15)5 <span class="smwwarning">[…]</span> -24H3,(H,63,77)(H,64,76)(H,65,79)(H,66,78) is too long. |
Has InChIKey | PMATZTZNYRCHOR-UHFFFAOYSA-N + |
Has KEGG Id | D00184 + |
Has Leadscope Id | LS-257 + |
Has PubChem CID | 5284373 + |
Has Smiles | C1(N[C@H](C(N(CC(N([C@H](C(N[C@@H](C(C)C)C(=O)N([C@H](C(N[C@@H](C)C(=O)N[C@@H](C(N([C@@H](C(N([C@H](C(N([C@@H](CC(C)C)C(N([C@H]1[C@@H]([C@@H](\C=C\C)C)O)C)=O)C)=O)CC(C)C)C)=O)CC(C)C)C)=O)C)=O)CC(C)C)C)=O)CC(C)C)C)=O)C)=O)CC)=O + |
Has category | Hepatotoxic + |
Has image | Cyclosporin_A.png + |
Has pKa | 9.45 + |
Has target | cyclophilin + |
Has toxic effect | Cholestasis + |