Reactome | Paracetamol ADME

Paracetamol ADME

Stable Identifier

R-HSA-9753281

DOI

10.3180/R-HSA-9753281.1

Type

Pathway

Species

Homo sapiens

Synonyms

Acetaminophen ADME, APAP ADME

ReviewStatus

5/5

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Paracetamol (APAP, aka acetaminophen or N-acetyl-p-aminophenol) is an analgesic drug used for to treat mild to moderate pain and as an antipyretic agent. It is one of the most widely used drugs in the world and is available alone or in combination with other drugs for pain relief, fever and allergy. It is thought to act through the inhibition of cyclooxygenases 1 and 2 (Graham et al. 2013, Esh et al. 2021). Paracetamol is generally safe at therapeutic doses but in overdose cases, it causes mitochondrial dysfunction and centrilobular necrosis in the liver which can lead to death.

APAP has a high oral bioavailability (~88%), is well absorbed and reaches peak blood concentrations after 90 minutes after ingestion. APAP binds plasma proteins to a small extent and has a plasma half-life of 1.5-3 hours. Most of the drug is eliminated by glucuronidate and sulfate conjugation (~55% and ~30% respectively) in the liver or as unchanged drug (~5%) (Forrest et al. 1982). A small amount (5-15%) is oxidised to the reactive metabolite N-acetyl-para-benzoquinone imine (NAPQI). NAPQI is usually detoxified by binding to liver glutathione but in overdose cases, glutathione is depleted and NAPQI instead, binds to sulfhydryl groups on proteins, leading to liver damage. ABCC2, ABCC3, ABCC4 and ABCG2 transporters mediate the efflux of APAP metabolites out of cells (McGill & Jaeschke 2013).

Literature References

PubMed ID	Title	Journal	Year
34278737	Pharmacological hypotheses: Is acetaminophen selective in its cyclooxygenase inhibition? Esh, CJ, Chrismas, BCR, Mauger, AR, Taylor, L	Pharmacol Res Perspect	2021
23719833	The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings Graham, GG, Davies, MJ, Day, RO, Mohamudally, A, Scott, KF	Inflammopharmacology	2013
23462933	Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis McGill, MR, Jaeschke, H	Pharm Res	2013
7039926	Clinical pharmacokinetics of paracetamol Forrest, JA, Clements, JA, Prescott, LF	Clin Pharmacokinet	1982