ABSTRACT
I. INTRODUCTION Since the liver plays such a central role in drug metabolism it is not surprising that this organ often is a target of adverse drug reactions. Despite extensive and rigorous testing of drugs in animals, hepatotoxicity in premarketing trials is a frequent cause of termination of a drug-development program. The fialuridine story is a recent example. Fialuridine was a promising drug for treatment of hepatitis B virus-associated chronic hepatitis yet proved to be extremely toxic in a phase II trial. The drug caused multisystem toxicity characterized by lactic acid acidosis, neuropathy, myopathy, and pancreatitis (1). Patients died of hepatic failure characterized by microvesicular steatosis, glycogen depletion, bile duct proliferation, and cholestasis (2). Hepatic toxicity was probably amplified by the enterohepatic cycling, which caused unpredicted high intrahepatic drug concentrations (3). The drug appeared to affect mitochondrial DNA. Thus successful animal tests do not always preclude toxicity in humans. An increasing number of drugs are taken off the market because of adverse drug reactions (4). Unexpected untoward effects are often due to drug-drug interactions or to prolonged use of a drug. Drug reactions may be rare but when these drugs are used in large populations, rare events may become relevant. An example is bromfenac with an incidence of hepatotoxicity of 1:20,000 when used longer than 10
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days. To find this in premarketing trials, the test population would have to be 100,000 persons on prolonged use. Also, diseases may change the behavior of a drug, in particular liver and renal diseases. The problem should not be underestimated as adverse drug reactions are estimated to rank among the top 10 causes of death in the United States and costs to the community vary between $30 and 130 billion annually (5,6). It would be of great benefit to patients, health care providers, and industry if tests could be developed that would detect a potential hepatotoxicity risk. A thorough knowledge of the way drugs are handled by the liver is a good starting point.
