Hepatotoxicity in drug development: detection, significance and solutions

Despite considerable progress in the understanding of the mechanism of liver toxicity we are not yet able to design non-hepatotoxic molecules rationally. Also, there is no "universal" in vitro primary screening approach for early identification of hepatotoxic molecules. In most cases hepatotoxicity is detected at later stages of drug development in animal toxicity studies or clinical trials. Although the liver is the most common target organ for drug candidates in animal toxicity studies, hepatotoxicity rarely leads to cessation of drug development during the preclinical phase. Indeed, contrary to other target organs, liver toxicity is usually reversible and can be monitored in man by sensitive serum enzyme tests. Therefore in many cases a compound found hepatotoxic in an animal species will be tested in man for a definitive assessment of its hepatotoxic potential. Liver toxicity in man may be acceptable when a drug has major therapeutic potential. In this situation mechanistic studies are essential to assess the risk in man and in some cases to identify protective agents. When liver toxicity leads to project termination a secondary screening approach may be envisaged if biologically active analogs are available.