Structure-Toxicity Relationships
ACTIVTox provides structural information related to toxicity
A common problem in drug development is that one member of a structural series displays toxicity that is not seen in other members of the family. Oftentimes, this is not discovered until late in the development process, causing unnecessary delays in bringing the new medicine to market. ACTIVTox provides a system in which to identify structure-based hepatotoxicity early in the process, when it can be easily and comparatively inexpensively remedied.
We have several examples of structure related toxicity to show you, click on the links to the right under Structure Families to see other examples.
Fluoroquinolone antibiotics
Figure 1. Structure of several fluoroquinolone antibiotics.
The fluoroquinolone antibiotics provide a system in which to test the ability of ACTIVTox to identify a know hepatotoxin among a series of related members. Figure 1 shows a number of these compounds, including the well known ciprofloxacin. Among this group, trovafloxacin is an hepatotoxin, while the others are not. A recent study from Liquori, et al., (1) showed that trovafloxacin initiated a unique set of gene expression changes in primary hepatocytes when compared to related fluoroquinolones. When we examined the set of fluoroquinolones in Figure 1 for toxicity using ACTIVTox, only trovafloxacin demonstrated activity. Moreover, examination of the structures points out the area of the molecule that is known to be metabolized by the liver.
Figure 2. ACTIVTox LDH release assay for six fluoroquinolones.
Only trovafloxacin among the compounds tested showed hepatotoxicity
Figure 2 shows the results of the LDH release assay using serial dilutions of six fluoroquinolone antibiotics. Only trovafloxacin is toxic. There is a large literature on the fluoroquinolones and there is significant information with regard to the effect of modifying each of the carbon molecules of the central structure (2). If we examine the structures shown in Figure 1, we see that the distinguishing feature of trovafloxacin is the R7 ring. Dalvie, et al., (3) have examined the metabolism of trovafloxacin and found that, in fact, metabolism to the acetate and the sulfate shown in Figure 3 are the principal metabolites formed in the liver. Our results suggest that subsequent metabolism of these compounds results in formation of the eventual toxin.
The experiment shown above was executed and analyzed in three days. ACTIVTox is designed for high throughput. By employing these assays early in the process, structural information can be obtained in real time, allowing feedback to the chemists.
Figure 3. Metabolites of trovafloxacin.
Other examples of structurally relevant toxicity information is available from Stem Cell Innovations.
References
- Liguori, MJ, et al. (2005) Microarray analysis in human hepatocytes suggests a mechanism for hepatotoxicity induced by trovafloxacin. Hepatology 41, 177 – 186.
- Mandell, L.A., P. Ball, and G. Tillotson (2001) Antimicrobial safety and tolerability: differences and dilemmas. Clinical Infectious Disease 32, supp. 1, S72 – S79.
- Dalvie, D.K., N. Khosla, and J. Vincent (1997) Excretion and metabolism of trovafloxacin in humans. Drug Metab. Disp. 25, 423 – 427.
