Figure 3.

The metabolism and renal excretion of acetaminophen and its metabolites. Approximately 50% of a therapeutic dose of acetaminophen is glucuronidated and excreted in the urine, approximately 40% is sulfated and excreted in the urine, and approximately 5% is excreted in the urine unchanged. The remaining 5% of ingested acetaminophen is oxidized by cytochrome enzymes (mainly CYP2E1) to produce acetaminophen N-hydroxamide, which is then converted to N-acetyl-p-benzoquinoneimine (NAPQI), a highly reactive and short-lived oxidation product or electrophile. Optimally, this dangerous metabolite is conjugated, and thereby detoxified, by glutathione. The glutathione-NAPQI conjugate is then cleaved to chemically stable, nontoxic thiol metabolites, including acetaminophen cysteine and acetaminophen mercapturate, which are largely excreted in the urine.