Pathway Acetaminophen Pathway, Pharmacokinetics

Stylized diagram showing acetaminophen metabolism and transport in the liver and kidney.
Acetaminophen Pathway, Pharmacokinetics
cyp1a2 cyp1a1 cyp2e1 cyp1a2 cyp2d6 cyp3a4 cyp2a6 sult1a1 sult1e1 sult1a4 sult1a3 sult2a1 ugt1a6 ugt1a1 ugt1a9 ugt2b15 gstp1 gstt1 abcc1 abcc4 abcc5 abcg2 abcb1 ptgs2 ptgs1 nat2 phenacetin phenacetin acetaminophen
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Description

Acetaminophen, also known as paracetamol or N-acetyl-p-aminophenol (APAP), is a common analgesic and antipyretic found in many over the counter medications. It is considered very safe when used at recommended doses but at higher doses causes hepatotoxicity [Article:14625346].

APAP metabolism occurs primarily in the liver. The principle routes of elimination are glucuronidation and sulfation although oxidation also occurs [Article:11215692].

Glucuronidation is the primary route in human adults, accounting for about 45-55% of APAP dose [Articles:11215692, 18232020]. This step can be catalyzed by UGT1A1, UGT1A6, UGT1A9, UGT2B15 in the liver [Articles:8494539, 11714888, 18232020, 21666065] and UGT1A10 in the gut [Article:15781124]. In human liver microsomes, UGT1A9 was the main enzyme responsible for catalysis at physiological drug concentrations with UGT1A6 more active at low concentrations and UGT1A1 more active at toxic concentrations [Article:11714888]. In vivo experiments looking at urinary metabolites in healthy volunteers showed a major role for UGT2B15 and lesser role for UGT1A6 [Article:21666065]. There are genetic variants in the UGT genes that may be of pharmacogenomic relevance (discussed below).

About 30-35% of metabolism of APAP occurs via sulfation [Article:18232020]. In adult human liver this is catalyzed by SULT1A1, SULT1A3, SULT1A4, SULT1E1 and SULT2A1 [Articles:18232020, 16517757, 12439736, 6573904]. The relative contributions of the different SULT enzymes are different in fetal and pediatric liver samples, with SULT1A3/4 and SULT1E1 accounting for the most variability in APAP metabolism [Article:18232020].

Bioactivation to form the N-acetyl-p-benzoquinone imine (NAPQI) is carried out by the CYP450 family of enzymes [Article:11215692]. In vitro experiments with expressed human proteins indicated that CYP3A4, CYP2E1, CYP2D6 and CYP1A2 are capable of APAP metabolism [Article:19219744]. Studies of human liver microsomes and specific inhibitors suggest that CYP2E1 and CYP2A6 are the most relevant for generation of toxic metabolites [Article:11866476].

The toxic metabolite NAPQI is detoxified first by glutathione conjugation in the liver, cataysed by the GST enzymes, then by acetylation in the kidneys, catalysed by N-acetyl transferase and then excreted in the urine [Article:11215692]. This process is enhanced by treatment with N-acetylcysteine, a precursor of glutathione (GSH), which is given in cases of APAP overdose [Article:22593093].

APAP is also transformed as it interacts with its target, prostaglandin H synthase [Article:16413237]. Prostaglandin H synthase is encoded for by two genes PTGS1 and PTGS2, also known as COX1 and COX2 because of the cyclooxygenase activity of the proteins. Both COX1 and COX2 proteins also have a peroxidase (POX) enzyme activity at a distinct site from the COX site. It is the POX part of the enzyme that binds APAP and modifies the drug. This results in inhibition of prostaglandin E production and pharmacodynamic effects (not discussed further in this pathway) [Article:16413237].

APAP is a metabolite of the prodrug phenacetin [Article:22949628]. Phenacetin was one of the first NSAIDs on the market but was withdrawn from the market in several countries due to nephrotoxicity [Article:3802594]. Continuous use was also associated with hypertension and cardiovascular risk. This is of interest given the current discussion on COX-2 inhibitors, their relative degrees of cardiovascular risk and the mechanisms by which risk is increased, in the wake of the market withdrawal of rofecoxib [Article:1984193]. Phenacetin is converted to APAP by CYP1A2 and CYP1A1 [Article:22949628].

Studies of mRNA and protein expression in livers from patients after toxic APAP ingestion showed upregulated efflux transporters of the ABC transporter family. ABCC1 and ABCC4 mRNA and ABCC4 and ABCC5 protein were upregulated at the sinusoidal membrane and ABCB1 and ABCG2 protein were upregulated at the canicular membrane compared to normal liver specimens [Article:17627974].

Authors: Caroline Thorn.
Citation:
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
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History:
Therapeutic Categories:
  • Pain, anti-inflammatory and immunomodulating agents

Entities in the Pathway

Genes (25)

Drugs/Drug Classes (2)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
acetaminophen acetaminophen-glucuronide UGT1A1, UGT1A6, UGT1A9, UGT2B15 11215692, 11714888, 15180166, 17164591, 18232020, 21666065, 8494539
acetaminophen acetaminophen-sulfate SULT1A1, SULT1A3, SULT1A4, SULT1E1, SULT2A1 18232020
acetaminophen NAPQI CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4 11866476, 19219744
acetaminophen NAPSQI PTGS1, PTGS2 16413237
acetaminophen-cysteine acetaminophen-NAC NAT2 11215692
acetaminophen-NAC acetaminophen-cysteine 11215692
NAPQI acetaminophen-cysteine GSTP1, GSTT1 22022436, 22175791
NAPSQI NAPQI 11215692
NAT2 NAT2 acetaminophen 9918139
phenacetin acetaminophen CYP1A1, CYP1A2 22949628
NAPQI 11215692, 11866476
acetaminophen-cysteine acetaminophen-cysteine 11215692
acetaminophen-cysteine acetaminophen-cysteine ABCC1, ABCC4, ABCC5 11215692, 17627974
acetaminophen-glucuronide acetaminophen-glucuronide ABCB1, ABCG2 17627974, 21241071
acetaminophen-sulfate acetaminophen-sulfate ABCB1, ABCG2 17627974, 21241071

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