Standard to Meet
| Compound Assessment
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Human Toxicity
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Compound causes cholestasis, lipid-accumulating disorders (steatosis/phopholipidosis) or cell death in humans.
| Causes cholestasis. In cases of death from hepatic failure, cell death is observed, with fibrosis associated with the cell death.
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Toxicity is concentration dependent (non-idiosyncratic).[1]
| Troglitazone toxicity is highly idiosyncratic.
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Therapeutic target.
| Troglitazone belongs to the thiazolidinedione class of peroxisome proliferator-activator receptor (PPAR) agonists. It is selective for PPARγ with weaker activity vs. PPARα. The desired pharmacology is insulin sensitization, but the full biological role of the PPAR class of nuclear hormone receptors is not yet understood.
Ref. Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A., Wilkison, W. O., Willson, T. M. & Kliewer, S. A. (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), J. Biol. Chem. 270, 12953-12956
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Biochemical mechanism of toxicity.
| Troglitazone itself causes direct inhibition of mitochondrial and other oxidative functions by the compound itself. In addition it is metabolized via multiple pathways to generate active metabolites, including quinones and inhibitors of hepatic anion transporters.
Refs:
1. Yasuhiro Masubuchi, “Metabolic and non-metabolic factors detremining troglitazone hepatotoxicity: a review”, Drug Metab Pharmacokinet 21(5) 744-56 (2006)
2. Tsuyoshi Yokoi J. Uetrecht (ed.), “Troglitazone”, Adverse Drug Reactions, Handbook of Experimental pharmacology 196, doi:10.1007/978-3-642-00663-0_14
, # Springer‐Verlag Berlin Heidelberg 2010
3. Hartmut Jaeschke Toxicol. Sci. “Troglitazone Hepatotoxicity: Are We Getting Closer to Understanding Idiosyncratic Liver Injury?” (2007) 97 (1): 1-3.
4. Mario Chojkier, “Troglitazone and liver injury: In search of answers”, Hepatology, Volume 41, Issue 2, pages 237–246, February 2005
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PK-ADME
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PK parameters: recommended dose, Cmax, Vd, and half-life.[2]
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Therapeutic window.[3]
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Metabolically activated (optional), active metabolite known and available for testing.[3]
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Omics and IC50 Data
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Gene expression profiles known.[4]
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Proteomics profiles known.[5]
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Metabonomics profiles known.[5]
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Fluxomics profiles known.[5]
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Epigenomics profiles known.[5]
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Observed IC50 for in vitro cellular efficacy.[5]
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Observed IC50 for in vitro cellular toxicity studies.
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Physical Properties
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Accepted and listed within the ToxCast/Tox21 program.[6]
| Included in phase II ToxCast List U.S EPA/ORD/NCCT. ToxCast Phase I and II Chemicals. December 14, 2010.
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Defined and confirmed structure and isomeric form(s).
| Troglitazone has two asymmetric carbons, one at the 2-position of the chroman ring and one at the 5-position of the thiazolidine ring in its molecule, and is produced as a mixture of equal amounts of four optical isomers.
Suzuki N, Takemura A, Miyamoto A, Yoshioka T, Tsutsumi S, Kawasaki T. Direct chiral separation of troglitazone stereoisomers using reversed-phase high-performance liquid chromatography. J Pharm Biomed Anal. 2002 Oct 15;30(3):823-36
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Substance stability.
| Troglitazone drug substance was not only proved to have no degradation, tested for 6 months storage at 40 °C , but also proved to be stable in solid state, retaining the ratio of the stereoisomers.
Suzuki N, Kasahara K, Hasegawa H, Kawasaki T. Physical property of troglitazone, an equal mixture of four stereoisomers. Int J Pharm. 2002; 248:71-80
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Soluble in buffer solution at 30 times the in vitro IC50 for toxicity.[7]
| Water solubility: 1.93 µg/ml (pH 7, room temperature)
Nicolaides E, Galia E, Efthymiopoulos C, Dressman JB, Reppas C. Forecasting the in vivo performance of four low solubility drugs from their in vitro dissolution data. Pharm Res. 1999; 16(12):1876-82
Water solubility: 5.2-12.8 µg/ml (pH 9, 37 °C)
Suzuki N, Kasahara K, Hasegawa H, Kawasaki T. Physical property of troglitazone, an equal mixture of four stereoisomers. Int J Pharm. 2002; 248:71-80
estimated intrinsic solubility : 8.3663E-4 mg/ml
estimated solubility in pure water at pH 6.03: 1.2372E-3 mg/ml
estimated solubility in water at pH 7.4: 9.28E-3 mg/ml
(Calculations performed using ACD/PhysChem v 9.14)
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Solubility in DMSO 100 times buffer solubility.
| 20 mg/ml Sigma Aldrich T2573 Product details
30 mg/ml Cayman Chemical Troglitazone Product details
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Vessel binding properties.[8]
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Commercial availability at > 95% (> 99% is preferred).
| Sigma Aldrich (T2573) 5mg/141.40€ purity >98% Sigma Aldrich T2573 Product details
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Vapor pressure. (Non-volatile)
| estimated vapor pressure: 1.81E-18 mmHg (Calculation performed using EPI Suite v4.10)
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Criteria Notes
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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. |
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