Pharmacokinetics

Acetaminophen, with a pKa of 9.5, is rapidly absorbed from the GI tract following oral administration. Peak plasma concentrations are observed within 30 minutes to 2 hours. Absorption is nearly complete following oral administration but varies with suppository forms of the drug. Acetaminophen is less plasma protein bound than the salicylates, although the amount bound varies from 20 to 50%. Following the use of normal therapeutic doses of acetaminophen, metabolism and conjugation to sulfate or glucuronides occurs, and clearance of these metabolites occurs in the kidney.A minor toxic metabolite is generated by the metabolism of acetaminophen via the P450 mixed-function oxidase system. This toxic metabolite is normally conjugated to glutathione in the liver and excreted via the kidney as conjugated cysteine and mercapturic acid. However, with the depletion of glutathione in certain disease states, such as liver cirrhosis and necrosis, and following chronic use of high doses of acetaminophen, this toxic reactive metabolite can accumulate and induce liver damage.

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