Where does acetaminophen metabolism primarily occur and what risk is associated with high doses?

Where does acetaminophen metabolism primarily occur and what risk is associated with high doses?

• A. Renal clearance with nephrotoxicity
• B. Cardiac metabolism with arrhythmias
• C. Hepatic metabolism with risk of hepatic failure due to NAPQI
• D. Gastrointestinal metabolism with ulcers

Answer: (C)

Metabolism of acetaminophen happens mainly in the liver. Most of the drug is converted by conjugation to glucuronide and sulfate, which are readily excreted. A smaller portion is processed by the liver’s cytochrome P450 system into a reactive metabolite called NAPQI. Under normal dosing, NAPQI is quickly neutralized by glutathione and detoxified. When doses are high, glutathione stores are overwhelmed, NAPQI accumulates and binds to cellular proteins, causing oxidative stress and hepatocyte injury that can progress to hepatic failure. This is why the primary risk with high doses is liver failure due to NAPQI toxicity. (Renal injury is possible in overdose but is not the primary concern; cardiac or GI metabolism is not the main issue here.)

Metabolism of acetaminophen happens mainly in the liver. Most of the drug is converted by conjugation to glucuronide and sulfate, which are readily excreted. A smaller portion is processed by the liver’s cytochrome P450 system into a reactive metabolite called NAPQI. Under normal dosing, NAPQI is quickly neutralized by glutathione and detoxified. When doses are high, glutathione stores are overwhelmed, NAPQI accumulates and binds to cellular proteins, causing oxidative stress and hepatocyte injury that can progress to hepatic failure. This is why the primary risk with high doses is liver failure due to NAPQI toxicity. (Renal injury is possible in overdose but is not the primary concern; cardiac or GI metabolism is not the main issue here.)