Paracetamol is metabolized primarily in the liver, where most of it (60–90% of a therapeutic dose) is converted to inactive compounds by conjugation with sulfate and glucuronide, and then excreted by the kidneys. Only a small portion (5–10% of a therapeutic dose) is metabolized via the hepatic cytochrome P450 enzyme system (specifically CYP2E1); the toxic effects of paracetamol are due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine, abbreviated as NAPQI) that is produced through this enzyme, not paracetamol itself or any of the major metabolites. The metabolism of paracetamol is an excellent example of toxication, because the metabolite NAPQI is primarily responsible for toxicity rather than paracetamol itself.
At usual doses, the toxic metabolite NAPQI is quickly detoxified by combining irreversibly with the sulfhydryl groups of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys.
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