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Zebrafish: an emerging technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug discovery
Article first published online: 29 JAN 2009
DOI: 10.1038/bjp.2008.249
2008 British Pharmacological Society
Issue
1476-5381/asset/cover.gif?v=1&s=f56f5a76559ff1cebf2b6e329fe028f1e9e0f463 "British Journal of Pharmacology")
British Journal of Pharmacology
Special Issue: Themed Issue: Safety Pharmacology: Guest Editor: Michael Pugsley
Volume 154, Issue 7, pages 1400–1413, August 2008
Additional Information
How to Cite
Barros, T. P., Alderton, W. K., Reynolds, H. M., Roach, A. G. and Berghmans, S. (2008), Zebrafish: an emerging technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug discovery. British Journal of Pharmacology, 154: 1400–1413. doi: 10.1038/bjp.2008.249
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Current address: Summit plc., 91 Milton Park, Abingdon, Oxfordshire, OX14 4RY, UK.
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Current address: Znomics Inc., 2611 SW 3rd Avenue, Suite 200, Portland, OR 97201, USA.
Publication History
- Issue published online: 29 JAN 2009
- Article first published online: 29 JAN 2009
- (Received May 16, 2008, Accepted May 23, 2008)
- Abstract
- Article
- References
- Cited By
Keywords:
- zebrafish;
- safety pharmacology;
- liability;
- high throughput;
- model organism
The zebrafish is a well-established model organism used in developmental biology. In the last decade, this technology has been extended to the generation of high-value knowledge on safety risks of novel drugs. Indeed, the larval zebrafish appear to combine advantages of whole organism phenotypic assays and those (rapid production of results with minimal resource engagement) of in vitro high-throughput screening techniques. Thus, if appropriately evaluated, it can offer undeniable advantages in drug discovery for identification of target and off-target effects. Here, we review some applications of zebrafish to identify potential safety liabilities, particularly before lead/candidate selection. For instance, zebrafish cardiovascular system can be used to reveal decreases in heart rate and atrial–ventricular dissociation, which may signal human ether-a-go-go-related gene (hERG) channel blockade. Another main area of interest is the CNS, where zebrafish behavioural assays have been and are further being developed into screening platforms for assessment of locomotor activity, convulsant and proconvulsant liability, cognitive impairment, drug dependence potential and impaired visual and auditory functions. Zebrafish also offer interesting possibilities for evaluating effects on bone density and gastrointestinal function. Furthermore, available knowledge of the renal system in larval zebrafish can allow identification of potential safety issues of drug candidates on this often neglected area in early development platforms. Although additional validation is certainly needed, the zebrafish is emerging as a versatile in vivo animal model to identify off-target effects that need investigation and further clarification early in the drug discovery process to reduce the current, high degree of attrition in development.
British Journal of Pharmacology (2008) 154, 1400–1413; doi:10.1038/bjp.2008.249; published online 16 June 2008