Acetaminophen metabolism

At therapeutic doses, 90 percent of acetaminophen is metabolized in the liver to sulfate and glucuronide conjugates that are then excreted in the urine. One-half of the remaining acetaminophen is excreted unchanged in the urine and one-half is metabolized via the hepatic cytochrome P450 (CYP2E1, CYP1A2, CYP3A4 subfamilies) mixed function oxidase pathway to N-acetyl-p-benzoquinoneimine (NAPQI), which is hepatotoxic. With normal doses (blue arrows), NAPQI is rapidly conjugated to hepatic glutathione, forming nontoxic cysteine and mercaptate compounds that are excreted in the urine. With toxic doses (red arrow), the sulfate and glucuronide pathways become saturated, resulting in an increased fraction of acetaminophen being metabolized by cytochrome P450 enzymes. Once glutathione stores are depleted, NAPQI begins to accumulate and hepatic injury ensues.