From ToxBankWiki
Vincristine:UserContributedInformation
Standard to Meet
| Compound Assessment
|
Human Toxicity
|
|
Compound causes cholestasis, lipid-accumulating disorders (steatosis/phopholipidosis) or cell death in humans.
| Summary: it is probable that this drug cuases hepatic injury in humans at high doses. However it is difficult to definitively state this for two reasons: generally it is co-administered with agents that can cause hepatic effects, and the dose limiting toxicity for the majority of patients is not hepatic.
Martindale does not list hepatotoxicity as an adverse effect associated with use of this drug. Following a review of the literature hepatotoxitiy has been seen in several clinical studies; however this drug is generally co-administered with other anti-neoplastic agents, many of which are hepatotoxic. It is therefore not possible to show a strong causal relationship between vincristine exposure and hepatotoxicity. Sega-Pondel et al (2007) report an analysis of adverse effects of cytostatic drugs in children with CNS tumours. That study showed no correlation between vincristine exposure and hepatotoxicity. The limitations of that study are the small sample size (17) and problems relating to co-administration of other agents. One study reports grade IV hepatotoxicity as a dose-limiting toxicity (Thomas et al 2009). However the strength of this association was relatively weak, with 1/7 patients at 2.4 mg/m2 affected by both increased transaminase and bilirubin levels compared with 0/18 at 2.25 mg/m2. 1/3 patients at 2 mg/m2 were affected by increased transaminase levels but no hyperbilirubinaemia (≤grade 2 hepatotoxicity). The authors did however note that the patient with grade IV hepatotoxicity also received fluconazole, which is a known hepatotoxin.
References
Martindale: Complete Drug Reference, 36th Edition
Sega Pondel et al (2007) Med Wieku Rozwoj 11:343-8 (Polish)
Thomas et al (2009) Cancer 115:5490-8
|
Toxicity is concentration dependent (non-idiosyncratic).
|
|
Therapeutic target.
| Tubulin Beta
|
Biochemical mechanism of toxicity.
| The antitumor activity of Vincristine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Vincristine may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca2+-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis.
|
|
PK-ADME
|
|
PK parameters: recommended dose, Cmax, Vd, and half-life.
| Cmax at recommended therapeutic dose : 374 ng/ml at 1.5mg/m2
References
Haim et al. Cancer Volume 73, Issue 10, pages 2515–2519, 1994
|
Therapeutic window.
|
|
Metabolically activated (optional), active metabolite known and available for testing.
|
|
|
Omics and IC50 Data
|
|
Gene expression profiles known.
| Buys TP, Chari R, Lee EH, Zhang M et al. Genetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cells.
Genes Chromosomes Cancer 2007 Dec;46(12):1069-79. Template:Pmd
Series GSE7556
Homo sapiens
Status Public on Aug 24 2007
Holleman A, Cheok MH, den Boer ML, Yang W et al. Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.
N Engl J Med 2004 Aug 5;351(6):533-42.
pmid:15295046
Series GSE635
Homo sapiens
Status Public on Aug 06 2004
Series GSE19290
Rattus norvegicus
Status Public on Jan 01 2010
Title Cardiotoxicity of tubulin binders
|
Proteomics profiles known.
|
|
Metabonomics profiles known.
|
|
Fluxomics profiles known.
|
|
Epigenomics profiles known.
|
|
Observed IC50 for in vitro cellular efficacy.
|
|
Observed IC50 for in vitro cellular toxicity studies.
|
|
|
Physical Properties
|
|
Accepted and listed within the ToxCast/Tox21 program.
| Not included in phase I and II ToxCast List [52]
No information on Tox21
Passes Toxcast criteria
0.023–50 μM, or 0.009–20 μM for CYP assays
soluble in DMSO (−1 < log P < 6, i.e., log of the octanol/water partition coefficient; 97.5% meet this criteria)
Log P experimental 2.82 (Drugbank)
molecular weight range 250–1000 (90% meet this criteria)
Vincristine 824.96 g/mol meets criteria
|
Defined and confirmed structure and isomeric form(s).
|
|
Substance stability.
| Solution should be stored protected from light [60]
|
Soluble in buffer solution at 30 times the in vitro IC50 for toxicity.
|
|
Solubility in DMSO 100 times buffer solubility.
| Estimated solubility in water at pH 7.4: 1.51e-2 mg/ml [57]
Vincristine sulfate salt water solubility: 50 mg/ml [61]
|
Vessel binding properties.
|
|
Commercial availability at > 95% (> 99% is preferred).
| Vincristine sulfate salt Sigma (V8388) 1mg/143.50€ purity: 95.0% TO 105.0% [61]
Vincristine sulfate salt Sigma (V8879) 1mg/122.00€ purity: 95.0% TO 105.0% [62]
|
Vapor pressure. (Non-volatile)
| Estimated vapor pressure 4.78E-29 mmHg [59]
|
|
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. |
|
|