From ToxBankWiki
Tamoxifen:UserContributedInformation
Standard to Meet
| Compound Assessment
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Human Toxicity
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Compound causes one or more of the following:- cholestasis
- steatosis
- phospholipidosis
- fibrosis
- cell death
in humans; or exemplifies an in vitro mechanism underlying one of these toxicities.
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Toxicity occurs via one or more of the following mechanisms:- mitochondrial disruption
- inhibition of lipid transport or metabolism
- nuclear receptor modulation
- complexation of phospholipids
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Therapeutic target.
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Biochemical mechanism of toxicity.
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PK-ADME
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PK parameters 1:
- recommended dose
- Cmax
- Vd
- half-life
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Therapeutic window.1
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Metabolically activated (optional), active metabolite known and available for testing.2
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Omics and IC50 Data
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Gene expression profiles known.3
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Proteomics profiles known.3
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Metabonomics profiles known.3
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Fluxomics profiles known.3
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Epigenomics profiles known.3
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Observed IC50 for in vitro cellular efficacy.4
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Observed IC50 for in vitro cellular toxicity studies. 4
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Physical Properties
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Accepted and listed within the ToxCast/Tox21 program.5
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Defined and confirmed structure and isomeric form(s).
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Substance stability.
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Soluble in buffer solution at 30 times the in vitro IC50 for toxicity.6
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Solubility in DMSO 100 times buffer solubility.
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Vessel binding properties.7
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Commercial availability at > 95% (> 99% is preferred).
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Vapor pressure. (Non-volatile)
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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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