Troglitazone

From ToxBankWiki

Troglitazone
Jump to: navigation, search

Troglitazone
Troglitazone.png
Identifiers
Leadscope Id LS-151313
CAS 97322-87-7
DrugBank APRD00488
ChemSpider 5389
Pathway DBs
KEGG D00395
Assay DBs
PubChem CID 5591
ChEMBL 408
Omics DBs
Properties
pKa 11.04
Stereo Racemic
ToxCast Accepted yes
Toxic Effect Cholestasis
ToxBank Accepted no
Target PPARa and PPARg


Executive Summary

Compound Troglitazone
Toxicities Cholestasis, cell death, and fibrosis
Mechanisms Direct inhibition of mitochondrial and other oxidative functions by the compound itself. Metabolized via multiple pathways to generate active metabolites, including quinones and inhibitors of hepatic anion transporters.
Comments Although troglitazone has been one of the major inducers of hepatotoxicity in clinical use, the toxicity is idiosyncratic. Any and all of several mechanisms may be manifested in different patient populations, and there is no consensus of a single primary cause of toxicity either in the clinic or in in vitro experiments. In addition, the biology of the PPARγ target is not fully understood and may contribute to ‘omics expression patterns in an uninterpretable manner. For these reasons, we recommend that any in vitro profile observed in SEURAT assays will not be interpretable in a predictive sense.
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.

SMILES CC1=C(C(=C2CCC(OC2=C1C)(C)COC3=CC=C(C=C3)CC4C(=O)NC(=O)S4)C)O
InChI

InChI=1S/C24H27NO5S/c1-13-14(2)21-18(15(3)20(13)26)9-10-24(4,30-21)12-29-17-7-5-16(6-8-17)11-19-22(27)25-23(28)31-19/h5-8,19,26H,9-12H2,1-4H3,(H,25,27,28)

InChI-Key

GXPHKUHSUJUWKP-UHFFFAOYSA-N

Supplier Sigma Aldrich
Summary Hepatotoxic Effects from the LIINTOP FP6 Program
Hepatocellular necrosis.gif Apoptosis.gif Transporter inhibition.gif Cholestatic.gif Steatotic.gif Phospholipidosis.gif Hepatocyte function.gif Mithochondria impairment.gif Oxidative stress.gif DNA synthesis genotoxicity.gif Covalent binding.gif Idiosyncrasia metabolic.gif Idiosyncrasia immune.gif Bioactivation required.gif LIINTOP severity.gif References
+ + +

[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]

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
Criteria Notes
1.
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.
2.
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.
3.
Literature data for at least one, but not necessarily all, of the ‘omics datasets is desired. This requirement can be waived in special cases.
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.
5.
This is not a requirement, but compounds utilized in the EPA testing program can be assumed to have physical properties verified to be suitable for in vitro cellular assays.
6.
Sparing soluble compounds may be assayed for solubility in serum and the percent serum used specified here.
7.
This property will be measured when a sample of compound becomes available.

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.

Toxicity Report

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
1 43.5926 bile duct stone
1 93.4934 hepatic haemorrhage
1 8.27834 hepatic necrosis
1 11.7025 hepatitis fulminant
1 8.7115 hyperbilirubinaemia
1 9.49286 metastases to liver

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 "Troglitazone" as an active ingredient.
FDA Label Search

PubMed references

The following resource link will perform a PubMed query for the terms "Troglitazone" and "liver toxicity".
Troglitazone Search

References

  1. Hynes, J., Marroquin, L.D., Ogurtsov, V.I., Christiansen, K.N., Stevens, G.J., Papkovsky, D.B., Will, Y., 2006. Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes. Toxicol. Sci. 92, 186–200.
  2. Ioannides, C., Lewis, D.F., 2004. Cytochromes P450 in the bioactivation of chemicals. Curr. Top. Med. Chem. 4, 1767–1788.
  3. Kang, P., Dalvie, D., Smith, E., Zhou, S., Deese, A., Nieman, J.A., 2008. Bioactivation of flutamide metabolites by human liver microsomes. Drug Metab. Dispos. 36, 1425–1437.
  4. Labbe, G., Pessayre, D., Fromenty, B., 2008. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam. Clin. Pharmacol. 22, 335–353.
  5. Li, A.P., 2002. A review of the common properties of drugs with idiosyncratic hepatotoxicity and the ‘‘multiple determinant hypothesis” for the manifestation of idiosyncratic drug toxicity. Chem. Biol. Interact. 142, 7–23.
  6. Masubuchi, Y., 2006. Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab. Pharmacokinet. 21, 347–356.
  7. Park, K., Williams, D.P., Naisbitt, D.J., Kitteringham, N.R., Pirmohamed, M., 2005b. Investigation of toxic metabolites during drug development. Toxicol. Appl. Pharmacol. 207, 425–434.
  8. Ioannides, C., Lewis, D.F., 2004. Cytochromes P450 in the bioactivation of chemicals. Curr. Top. Med. Chem. 4, 1767–1788.
  9. Kang, P., Dalvie, D., Smith, E., Zhou, S., Deese, A., Nieman, J.A., 2008. Bioactivation of flutamide metabolites by human liver microsomes. Drug Metab. Dispos. 36, 1425–1437.
  10. Li, A.P., 2002. A review of the common properties of drugs with idiosyncratic hepatotoxicity and the ‘‘multiple determinant hypothesis” for the manifestation of idiosyncratic drug toxicity. Chem. Biol. Interact. 142, 7–23.
  11. Park, K., Williams, D.P., Naisbitt, D.J., Kitteringham, N.R., Pirmohamed, M., 2005b. Investigation of toxic metabolites during drug development. Toxicol. Appl. Pharmacol. 207, 425–434.
  12. Reddy, M.V., Storer, R.D., Laws, G.M., Armstrong, M.J., Barnum, J.E., Gara, J.P., McKnight, C.G., Skopek, T.R., Sina, J.F., DeLuca, J.G., Galloway, S.M., 2002. Genotoxicity of naturally occurring indolecompounds: correlation between covalentDNAbinding and other genotoxicity tests. Environ. Mol. Mutagen. 40, 1–17.
  13. 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.
  14. 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.
  15. 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.
  16. Palmeira, C.M., Rolo, A.P., 2004. Mitochondrially-mediated toxicity of bile acids. Toxicology 203, 1–15.
  17. Pauli-Magnus, C., Meier, P.J., 2006. Hepatobiliary transporters and drug-induced cholestasis. Hepatology 44, 778–787.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. Zollner, G., Trauner, M., 2008. Mechanisms of cholestasis. Clin. Liver Dis. 12, 1–26 (vii).
  23. 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.
  24. 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.
  25. 25.0 25.1 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.
  26. Literature data for at least one, but not necessarily all, of the ‘omics datasets is desired. This requirement can be waived in special cases.
  27. 27.0 27.1 27.2 27.3 27.4 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.
  28. 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.
  29. Sparing soluble compounds may be assayed for solubility in serum and the percent serum used specified here.
  30. This property will be measured when a sample of compound becomes available.

Calculated/Predicted Properties

Water Solubility Results
pH Sol,mg/ml 0 25- 25-,26- Graph
2 8.37E-4 100 - - Troglitazone solubility.png
5.5 9.55E-4 87.5 12.5 -
6.5 2.00E-3 41.2 58.8 -
7.4 9.28E-3 8.1 91.9 -
10 8.55E-2 - 95.7 4.3
Summary Solubility Data
Intrinsic Solubility,mg/ml 8.3663E-4
Intrinsic Solubility,log(S,mol/l) -5.7224
Solubility in Pure Water at pH = 6.03,mg/ml 1.2372E-3
Calculations performed using ACD/PhysChem v 9.14
LogD Results
pH LogD Graph
2 4.98 Troglitazone logd.png
5.5 4.93
6.5 4.61
7.4 3.94
10 2.98
Calculations performed using ACD/PhysChem v 9.14
Single-valued Properties
Property Value Units Error
LogP 4.98 0.79
MW 441.54 -
PSA 110.16 -
FRB 6 -
HDonors 2 -
HAcceptors 6 -
Rule Of 5 0 -
Molar Refractivity 120.47 cm3 0.3
Molar Volume 348.53 cm3 3
Parachor 931.5 cm3 6
Index of Refraction 1.61 0.02
Surface Tension 51.02 dyne/cm 3
Density 1.27 g/cm3 0.06
Polarizability 47.76 10E-24 cm3 0.5
Calculations performed using ACD/PhysChem v 9.14
Property Name Value Units Source
pKa 11.04 SPARC v4.5
Estimated VP 1.81E-18 mm Hg EPI Suite v4.10
Estimated VP 2.41E-16 Pa EPI Suite v4.10
Estimated Water Solubility 0.03863 mg/L EPI Suite v4.10
WATERNT Frag Water Solubility Estimate 0.054832 mg/L EPI Suite v4.10
pKa Results
Acidic/Basic Acidic/Basic Aparrent pKa Value Error
26 A 11.35 0.4
25 MA 6.34 0.5
25 MB -5.53 0.4
A = Acidic
B = Basic
MA = Most Acidic
MB = Most Basic
Calculations performed using ACD/PhysChem v 9.14

Authors of this ToxBank wiki page

David Bower, Egon Willighagen, Matthew Clark
Facts about TroglitazoneRDF feed
Accepted by ToxBankno  +
Accepted by ToxCastyes  +
Equivalent URIThis property is a special property in this wiki.http://bio2rdf.org/drugbank_drugs:APRD00488  +, http://bio2rdf.org/cas:97322-87-7  +, http://www.chemspider.com/Chemical-Structure.5389.rdf  +, http://bio2rdf.org/pubchem:5591  +, http://bio2rdf.org/dr:D00395  +, and http://rdf.openmolecules.net/?InChI=1S/C24H27NO5S/c1-13-14(2)21-18(15(3)20(13)26)9-10-24(4,30-21)12-29-17-7-5-16(6-8-17)11-19-22(27)25-23(28)31-19/h5-8,19,26H,9-12H2,1-4H3,(H,25,27,28)  +
Has CAS97322-87-7  +
Has ChEMBL Id408  +
Has ChemSpider Id5389  +
Has DrugBank IdAPRD00488  +
Has InChIInChI=1S/C24H27NO5S/c1-13-14(2)21-18(15(3)20(13)26)9-10-24(4,30-21)12-29-17-7-5-16(6-8-17)11-19-22(27)25-23(28)31-19/h5-8,19,26H,9-12H2,1-4H3,(H,25,27,28)  +
Has InChIKeyGXPHKUHSUJUWKP-UHFFFAOYSA-N  +
Has KEGG IdD00395  +
Has Leadscope IdLS-151313  +
Has PubChem CID5591  +
Has Smilesc12c(CC[C@@](O1)(COc1ccc(C[C@@H]3C(NC(S3)=O)=O)cc1)C)c(c(O)c(c2C)C)C  +
Has StereoRacemic  +
Has categoryHepatotoxic  +
Has imageTroglitazone.png  +
Has pKa11.04  +
Has targetPPARa and PPARg  +
Has toxic effectCholestasis  +
See alsohttp://dx.doi.org/10.1007%2F978-3-642-00663-0_14  +
Personal tools
Namespaces
Variants
Actions
Navigation
Hepatotoxins
Cardiotoxins
Renal Toxins
Special Substances
Undifferentiated Stem Cells
hiPSC Lines
Liver Cell Lines
iPS-derived Cardiomyocytes
Reagents (Growth Factors)
Reagents (Antibodies)
Reagents (Others)
Suppliers (Cells)
Toolbox