Do Plasma Concentrations of Acetaminophen and its Conjugated Metabolites Reflect Concentrations in Various Tissues?
The mild analgesic drug acetaminophen (N-acetyl-p-aminophenol, APAP) is hepatotoxic in large doses (1). The major pathways for elimination of APAP are by conjugation to glucuronic acid and sulfate. A smaller fraction of the drug is converted in the liver via cytochrome P-450(s) to a reactive, potentially toxic metabolite (1). This metabolite is detoxified by conjugation to glutathione, (α-L-glutamyl-L-cysteinylglycine) in liver cells (2). When the glutathione concentration in the liver is low, increased amounts of the reactive metabolite(s) of APAP bind covalently to cellular macromolecules and this apparently leads to hepatic necrosis. The glutathione conjugate of acetaminophen (A-GSH) formed in the liver is excreted primarily in the bile (3). This conjugate is then converted to the cysteine (A-Cys) and mercapturic acid (A-Mercap) conjugates of APAP and these substances are excreted in urine. The sites in the body for the catabolism of A-GSH to form A-Cys and the conversion of A-Cys to A-Mercap have not been entirely identified.
KeywordsPlasma Concentration Glucuronic Acid Unchanged Drug Hepatic Necrosis Reactive Metabolite
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