hepatotoxicity

Hepatotoxicity is drug-induced injury to the liver, the body's main chemical-processing factory. Because the liver receives the full dose of an oral drug first and is the primary site where drugs are broken down, it is heavily exposed and especially vulnerable to harm.

Liver injury can arise through several routes. A drug or, more often, a reactive metabolite formed during metabolism can chemically attack liver proteins, deplete protective molecules like glutathione, or trigger immune attack on liver cells. The classic textbook example is acetaminophen overdose, where a normally minor reactive metabolite overwhelms the liver's defenses.

Drug-induced liver injury is one of the leading causes of drug failure and of drugs being pulled from the market. It is hard to predict because much of it is rare and idiosyncratic, varying unpredictably between individuals. Discovery teams watch for high reactive-metabolite formation, high daily dose, and lipophilicity, all of which raise the odds of liver toxicity.