The liver is an important indicator of drug toxicity. It deals with toxins and many medicinal products that pass through the body, and as such, has a high chance of being exposed to drug toxicity. More than 900 drugs, toxins and herbs are known to cause liver injury1. Hepatic injury is a common reason for drug withdrawal, but can be difficult to detect as many drugs only cause it infrequently2.
The Safety Intelligence Program (SIP) is a knowledgebase of comprehensive intelligence, built from a wide set of public domain sources, around compounds causing adverse effects in tissues, including effects on biomarkers of tissue injury and also molecular mechanisms.
The data in SIP can be accessed via both drug class and chemical structure searches, meaning that drugs with similar structures and other properties can be compared to a drug in development. This means that potential hepatotoxicity could be detected earlier in the drug development process, which could potentially lead to large savings.
Through SIP (as of 11th of June 2012), it is possible to access the following:
- 95,000 assertions related to the liver, from more than 11,000 compounds (Figure 1).
- More than 8,000 biomedical observations related to the liver, including hepatic fibrosis, liver failure and hepatic necrosis (Figure 2).
- A variety of species, including humans and model organism such as rats, allowing for cross-species comparison (Figure 3).
- Data curated from a wide range of sources, including Medline, DailyMed and regulatory documents from the FDA.
Figure 1 shows that the compound in SIP most associated with liver effects is ethanol. Its effects include hepatic injury, hepatic apoptosis and steatosis. Other liver toxicants include Phenobarbital, which causes liver cancer and liver cirrhosis, and Ciclosporin, which is associated with hepatotoxicity, cholestasis and altered hepatic function.
Of the approximately 8,000 liver observations featured in SIP, the most common adverse effects are hepatotoxicity (most assertions in humans), hepatic injury (mostly in humans) and hepatocellular carcinoma (mostly in rats), as shown in Figure 2. SIP also includes a wide variety of physiological observations associated with the liver, including enzyme function, RNA synthesis and liver weight. By allowing the detection of altered physiology for a given chemical search, potential toxicities can be predicted in the absence of pathological findings.
Where possible, the species is reported with each assertion for a range of mammals (examples provided in Figure 3). Rat studies constitute the greatest proportion of liver assertions in SIP, followed by reports in humans (43k and 24k assertions respectively). In cases where the species cannot be accurately determined, the “other” species category is used.
References
- http://emedicine.medscape.com/article/169814-overview
- http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf
For more information on the Safety Intelligence Program, please visit instem.com or contact sip@instem.com to understand how you can access this important resource for liver tox/path knowledge.