Metabolism of acetaminophen

Many process mixtures, notably fermentations, require sample preconcentration, microdialysis, microfiltration, or ultrafiltration prior to analysis. A capillary mixer has been used as a sample preparation and enrichment technique in microchromatography of polycyclic aromatic hydrocarbons in water.8 Microdialysis to remove protein has been coupled to reversed phase chromatography to follow the pharmacokinetics of the metabolism of acetaminophen into acetaminophen-4-O-sulfate and acetaminophen-4-O-glucu-ronide.9 On-line ultrafiltration was used in a process monitor for Aspergillus niger fermentation.10... 

Johnson, K. A. Plumb, R. Investigating the human metabolism of acetaminophen using UPLC and exact mass oa-TOF MS. J Pharm Biomed Anal 2005. 

Figure 8.6 Metabolism of acetaminophen and formation of reactive metabolites.

Metabolism of acetaminophen (Ac) to hepatotoxic metabolites. (GSH, glutathione GS, glutathione moiety Ac, reactive intermediate.)... 

Sweeny, D.J. and Weiner, M., Metabolism of acetaminophen in hepatocytes isolated from mice and rats of various ages, Drug Metab. Dispos., 13, 377, 1985. 

Perhaps N-acetylcysteine would conjugate to some of the N-acetyl-p benzoquinone imine that is produced by the metabolism of acetaminophen, thereby preventing the depletion of the liver s supply of glutathione. 

Oxidative metabolism of acetaminophen by the cytochrome P450 system, shown in Figure 40-3, is catalyzed by various cytochromes P450 such as CYP2E1 and others. The deleterious product is A-acetyl benzo-quinoneimine, an unstable intermediate shown in Figure 40-3, which can... 

Figure 4-1. Metabolism of acetaminophen to harmless conjugates or to toxic metabolites. Acetaminophen glucuronide, acetaminophen sulfate, and the mercapturate conjugate of acetaminophen are all nontoxic phase II conjugates. Ac is the toxic, reactive phase I metabolite. Transformation to the reactive metabolite occurs if hepatic stores of sulfate, glucuronide, and glutathione are depleted or overwhelmed or if phase I enzymes have been induced.

Fig. 3 Bioactivation of model hepatotoxins. The stractures of the toxic metabolites that are formed from oxidative metabolism of acetaminophen, bromobenzene, carbon tetrachloride, and furosemide are given alongside the requirement for GSH depletion and covalent binding...

Corcoran GB, Todd EL, Racz WJ, Hughes H, Smith CV, Mitchell JR (1985) Effects of N-acetyicysteine on the disposition and metabolism of acetaminophen in mice. J Pharmacol Exp Ther 232 857-863... 

A. Hepatic injury. One of the products of normal metabolism of acetaminophen by cytochrome P-450 mixed-function oxidase enzymes is highly toxic normally this reactive metabolite (NAPQI) is rapidly detoxified by glutathione in liver cells. However, in an overdose, production of NAPQI exceeds glutathione capacity and the metabolite reacts directly with hepatic macromolecules, causing liver injury. 

Schenker S, Speeg KV, Perez A, Finch J. The effects of food restriction in man on hepatic metabolism of acetaminophen. Clin Nutr (200 ) 20,145-50. 

Esteban A, Perez-Mateo M, Boix V, Gonzalez M, Portilla J, Mora A. Abnormalities in the metabolism of acetaminophen in patients infected with the human immunodeficiency virus QilV). Methods Find Exp Clin Pharmacol ( 991) 19, 129-32. 

GwUt, P, C. Lear, M. Temjrero, et aL 1994. The effect of garlic extract on human metabolism of acetaminophen. Cancer Epidemiol. Biomarkers. Prev. 3 155-160. 

Glutathione conjugation also occurs in the metabolism of acetaminophen (Tylenol ). Metabolic oxidation produces an N-acetylimidoquinone intermediate, which is highly reactive. 

Additionally, Finley et al. (12) had discussed the specificity of reacting positions on benzene ring of iV NT-quinonediimine against a nucleophilic substitution. It was proposed that the 1-, 3- and 5-positions of N/P-quinonediimine ring was highly susceptible to nucleophilic substitution. Actually, it has been reported in metabolism of acetaminophen (13-16) that the 3- and 5-positions of quinoneimine is highly reactive to the nucleophilic attack by glutathione (GSH). 

Acetaminophen is a widely used analgesic. Pretreatment with APAP followed by ethanol intake increases the metabolism of acetaminophen and thereby its toxicity. Binge drinking of ethanol increases the hepatotoxicity of acetaminophen [8]. Caffeine also activates the metabolism of acetaminophen and it, too, increases the hepatotoxicity of acetaminophen. The combination of ethanol and caffeine significantly increases the fiver toxicity of acetaminophen [9]. 

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