Acetaminophen Metabolism After Major Surgery: A Greater Challenge With Increasing Age

Abstract

Patients undergoing major surgery represent a good model for the study of the hepatic metabolism of acetaminophen (APAP) after surgery and for the evaluation of how the detoxification process is influenced by aging. Thirty patients received intravenous APAP (1 g/6 h) for 4 days (D1-D4). Daily 24-h urinary metabolites-cysteine-APAP, mercapturate-APAP, APAP, and glucuronide and sulfate conjugates-as well as blood glutathione levels were compared with repeated-measures analysis of variance (significance, P<0.05). Between D1 and D4, cysteine-APAP increased (308±308 mg vs. 570±512 mg, P=0.005), and sulfate and glucuronide conjugates decreased (1,365±1,084 mg vs. 694±600 mg, P<0.0001 and 2,418±817 mg vs. 1,513±1,076 mg, P=0.011, respectively). Blood glutathione decreased (790±125 vs. 623±132 µmol/l, P<0.0001. These changes increased with aging. APAP disposition after major surgery shifts toward the oxidative pathways of metabolism, and this is enhanced with aging. Supplementation with sulfur-containing amino acids should be investigated further as it might minimize the effect on antioxidant defenses, especially in older persons undergoing more extensive surgical procedures.

Acetaminophen metabolism after liver resection: A prospective case–control study

“…These findings are similar to those of Pickering et al (12) who quantified the levels of urinary metabolites after major abdominal (aortic) surgery. In this study, as in ours, a rise in the glutathione dependent metabolites cysteine and mercapturate was observed when compared to early post-operative levels.…”

Intravenous Paracetamol as an Antipyretic and Analgesic Medication: the Significance of Drug Metabolism

“…UTG1A6 is catalyzing the glucuronidation of paracetamol and these haplotypes encode for enzymes with different activity (14,15). Other factors, like age, seem also to impose considerably on the rate of formation of N-sulfate-APAP (16). The presented findings indicate that patients who failed to become afebrile with the first dose of paracetamol, reached defervescence with paracetamol as a rescue medication much slower compared to those administered other agents.…”

N‐acetylcysteine prevents glutathione decrease and does not interfere with paracetamol antinociceptive effect at therapeutic dosage: a randomized double‐blind controlled trial in healthy subjects

“…The literature has widely reported that an overdose of APAP as well as therapeutic doses in patients with chronic disease and poor stores of GSH (alcoholism, malnutrition…) may lead to liver dysfunction and/or acute liver failure. A large diminution of whole blood GSH concentration has also been shown after heavy surgery with a few days of 4 g APAP a day. These present findings in young volunteers underline in a healthy population the silent, not readily visible, and poorly acknowledged impact of APAP on GSH stores at therapeutic doses.…”

“…It is primarily metabolized in the liver by phase I and II enzymes. Oxidative phase I reactions typically involve several CYP450 isoforms, that catalyze the oxidation of paracetamol to NAPQI (N‐acetyl‐ p ‐benzo‐quinone imine), a toxic metabolite buffered by glutathione (GSH) . Phase II reactions, glucuronidation and sulfation participate to the elimination of the drug.…”