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MARCH: NCTR RESEARCH HIGHLIGHTS
Searching for Molecular Biomarkers of Liver Toxicity
Liver toxicity is one of the most common causes for the recall of drugs that have been approved by the FDA for use in humans. Preclinical (animal) studies are used to determine if drugs may be toxic, and the liver is a major target organ of early screening efforts in the pharmaceutical industry. In spite of this, there have been a number of instances in which drugs that gave no indication of liver toxicity in preclinical studies turned out to be toxic to the liver after being approved for marketing.
The goal of a CRADA just initiated with BG Medicine is to create new tools, termed molecular biomarkers, that can be used in preclinical and clinical studies to predict potentially harmful effects of drugs in humans.
This will be accomplished by treating rats orally for 28 days with a pair of similar drugs, one of which causes liver toxicity in humans. The first pair to be investigated includes tolcapone, which was discovered to cause liver toxicity only after being approved for use in humans, and entacapone, which has not shown any indications of causing liver toxicity. During the first days of administering the drugs, urine will be collected and analyzed to determine if there are certain metabolites that are unique to the drug (tolcapone) that causes liver toxicity. After 28 days of treatment, the rats will be humanely killed and various techniques will be used to analyze their urine, blood, and liver with the goal of determining if certain parameters are unique in the rats administered the drug (tolcapone) that causes liver toxicity. If successful, the molecular biomarkers developed during the course of this study can then be applied during drug development to prevent the inadvertent administration of drugs that cause liver toxicity to humans.
For further information, contact Dr. Fred Beland, Director, Division of Biochemical Toxicology, NCTR.