Zebrafish: An emerging whole-organism screening tool in safety pharmacology

Abstract

During the last two decades, the development in drug discovery is slackening due to drug withdrawal from the market or reported to have postmarket safety events. The vital organ toxicities, especially cardiotoxicity, hepatotoxicity, pulmonary toxicity, and neurotoxicity are the major concerns for high drug attrition rates. The pharmaceutical industry is looking for high throughput, high content analysis based novel assays that would be fast, efficient, reproducible, and cost-effective; would address toxicity, the safety of lead molecules, and complement currently used cell-based assays in preclinical testing. The use of zebrafish, a vertebrate screening model, for preclinical testing is increasing owing to the number of advantages and striking similarities with the mammal. The zebrafish embryo development is fast and all vital organs such as the heart, liver, brain, pancreas, and kidneys in zebrafish are functional within 96-120hpf. The maintenance cost of zebrafish is reasonably low as compared to mammalian systems. Due to these features, zebrafish has arisen as a potential experimental screening model in lead identification and validation in the drug efficacy, toxicity, and safety evaluation. Numbers of drugs and chemicals are screened using zebrafish embryos, and results were found to show 100% concordance with mammalian screening data. The application of zebrafish, being a whole-organism screening model, would show a significant reduction in the cost and time required in the drug development process. The present challenge includes complete automation of the zebrafish screening model, i.e., from sorting, imaging of embryos to data analysis to accelerate the therapeutic target identification, and validation process.

Keywords: Drug discovery; high content analysis; high-throughput screening; organ-specific toxicity; safety pharmacology; zebrafish.

Figure 1

Data of new drug approvals by the US FDA between 1998 and 2017[1234] (a) Bar graph depicts new drugs (new molecular entities- chemicals and biological) approved by the US FDA for a period of two decades (1998–2017). The number of drugs approved during this period and later withdrawn or associated with postmarket safety events is depicted by bar graph and line graph, respectively. (b) The different types of toxicities associated with approved drugs in 1998–2017 are denoted

Figure 2

Comparison of in vitro and in vivo whole-organism models

Figure 3

The developmental stages of zebrafish from 0 h embryos, 72 hpf and 5 dpf

Figure 4

Schematic representation of (a) Two-chamber zebrafish heart and (b) electrocardiogram