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Hepatotoxicity can be considered to occur in two forms, symptomatic or idiosyncratic.
Drugs or toxins that have a symptomatic hepatotoxicity are those that have predictable dose-response curves (higher concentrations cause more liver damage) and well characterized mechanisms of toxicity.
In contrast, idiosyncratic hepatotoxins are agents that cause liver damage in only a small fraction of the population that is exposed to the agent, does not have a clear dose-response or temporal relationship, and most often do not have predictive models. Idiosyncratic hepatotoxicity has led to the withdrawal of several drugs from market even after rigorous clinical testing as part of the FDA approval process (troglitazone, Rezulin®). Ranitidine (Zantac®), and trovafloxacin (Trovan®) are two excellent examples of idiosyncratic hepatotoxins).
The main cause: acetaminophen
One of the main causes of drug-induced hepatotoxicity in western countries is acetaminophen (paracetamol) poisoning, which is a symptomatic hepatotoxin. Hepatic damage can sometimes be detected at advanced stages by the typical yellow skin (jaundice) that arises from defective bilirubin liver metabolism. For earlier stages, there are a number of convenient liver function tests. Acetylcysteine can limit the severity of the liver damage by capturing the toxic acetaminophen metabolite.
Many common drugs are metabolised by the liver in significant amounts. This, together with its role as first filter of blood loaded with substances absorbed from the gut, makes hepatotoxicity one of the main concerns of pharmaceutical companies in their research for new drugs. All lead optimisation cascades must deal in some way with the issue of hepatic toxicity. An especially thorny issue is enterohepatic circulation . Entero-hepatic circulation is the excretion of the drug (or a metabolite of it) through the bile to be re-absorbed in the gut and sent again to the liver along the portal vein, so the excretion-reabsortion cycle can start again. Due to this process, some molecules not too toxic as such may become extremely destructive as they can reach unexpectedly high hepatic concentrations, or prolonged permanence in the entero-hepatic system.
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