• Acetaminophen

This drug is popular because it generally is well tolerated, without much in the way of side effects, and is able to both lower fever and relieve pain, two benefits often sought from medicines. The BUT, is one that applies to how the drug is broken down in the body.

Acetaminophen is predominantly metabolized by conjugation reactions to form sulfate and glucuronide metabolites, which are excreted in the urine. A lesser amount of the drug is metabolized by cytochrome P450 2E1 to form NAPQI, which is rapidly bound to intracellular glutathione and excreted in the urine as mercapturic acid. When excessive amounts of acetaminophen are ingested, the ability to conjugate is overwhelmed and metabolism by cytochrome P450 2E1 becomes of much greater importance. In these situations, the capacity of glutathione to serve as an effective hepatoprotectant may be overwhelmed, and the hepatocyte becomes relatively defenseless against attack by the reactive intermediates. Two important factors determine the likelihood of production of hepatic injury by acetaminophen: the amount of NAPQI produced by P450 2E1 and the availability of glutathione as a hepatoprotectant. The intracellular concentration of NAPQI and dose of acetaminophen ingested are clearly associated. However, there is more to the story than simply dosage. Factors that affect the production of cytochrome P450 2E1 and of glutathione are of importance. With chronic ingestion of alcohol, doses of acetaminophen near or even with the suggested therapeutic range may lead to liver injury, promoted by an alcohol-induced decrease in intracellular glutathione and possibly an increase (actual or relative to GSH) of cytochrome P450 2E1. The end result is overproduction of NAPQ1 relative to the dispositional pathway of GSH leading to a heightened likelihood of liver damage.

"Many discussions have occurred at the U.S. Food and Drug Administration regarding labeling and the need for increased awareness of risks by the public. There is general agreement that an overdose of acetaminophen is more likely to cause liver injury in a patient who is a chronic alcoholic. The debate is the definition of overdose and the amount of alcohol ingestion needed to predispose the patient to injury." [Maddrey WC. Drug-induced hepatotoxicity: 2005. Journal of Clinical Gastroenterology. 39(4 Suppl 2):S83-9, 2005]

• Medline Plus on acetaminophen

• Mayo Clinic - Advice on how to avoid overdosing your child with acetaminophen