Acetaminophen protein adducts in the circulation are a specific biomarker of acetaminophen oxidation, and may be a more sensitive measure of impending hepatic injury following overdose than alanine transaminase (ALT). We performed an exploratory analytical substudy of adducts during a clinical trial (NACSTOP) of abbreviated (12-hour) versus control (20-hour) acetylcysteine to identify any signal of diminished antidotal effectiveness with shortened therapy.
We measured adducts at 0, 12, and 20 hours from a convenience sample of subjects enrolled in the cluster-controlled NACSTOP trial evaluating a 12-hour (“abbreviated”; 200 mg/kg over 4 hours, 50 mg/kg over 8 hours) vs 20-hour acetylcysteine regimen (“control”; 200 mg/kg over 4 hours, 100 mg/kg over 16 hours). Adducts were assayed using high-performance liquid chromatography/mass spectrometry.
Median ALT 20 hours after the initiation of acetylcysteine was 12 U/L (IQR 8,14) in the abbreviated 12-hour regimen group (N = 8), compared with the control group 16 U/L (IQR 11,21; N = 21) (p = 0.46). Adduct concentrations were similarly low in both groups: abbreviated [(0.005 μmol/L, IQR (0,0.14)] and control [(0.005 μmol/L, IQR (0,0.05)] (p = 0.61).
There were minimal to no acetaminophen protein adducts detected. These findings further support discontinuing acetylcysteine when acetaminophen concentrations are low and liver function tests normal after 12 hours of treatment.
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Wong A, McNulty R, Taylor D, Sivilotti M, Greene S, Gunja N, et al. The NACSTOP trial: a multicenter, cluster-controlled trial of early cessation of acetylcysteine in acetaminophen overdose. Hepatology. 2019;69(2):774–84.
Pettie J, Caparrotta TM, Hunter RW, et al. Safety and efficacy of the SNAP 12-hour acetylcysteine regimen for the treatment of paracetamol overdose. EClinicalMed. 2019.
Johnson MT, McCammon CA, Mullins ME, Halcomb SE. Evaluation of a simplified N-acetylcysteine dosing regimen for the treatment of acetaminophen toxicity. Ann Pharmacother. 2011;45(6):713–20.
Chiew AL, Isbister GK, Kirby KA, Page CB, Chan BSH, Buckley NA. Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2). Clin Toxicol. 2017;55(10):1055–65.
Dart RC, Rumack BH. Patient-tailored acetylcysteine administration. Ann Emerg Med. 2007;50(3):280–1.
Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol. 2002;40(1):3–20.
Sivilotti ML, Yarema MC, Juurlink DN, Good AM, Johnson DW. A risk quantification instrument for acute acetaminophen overdose patients treated with N-acetylcysteine. Ann Emerg Med. 2005;46(3):263–71.
Mitchell JR, Jollow DJ, Potter WZ. Acetaminophen induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther. 1973;187(1):185–94.
Davern ITJ, James LP, Hinson JA, Polson J, Larson AM, Fontana RJ, et al. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology. 2006;130(3):687–94.
Heard K, Green JL, Anderson V, Bucher-Bartelson B, Dart RC. Paracetamol (acetaminophen) protein adduct concentrations during therapeutic dosing. Br J Clin Pharmacol. 2016;81(3):562–8.
Wong A, Graudins A. Simplification of the standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning results in a lower incidence of adverse drug reactions. Clin Toxicol. 2016;54(2):115–9.
McNulty R, Lim JME, Chandru P, Gunja N. Fewer adverse effects with a modified two-bag acetylcysteine protocol in paracetamol overdose. Clin Toxicol. 2018;56(7):618–21.
Schmidt LE, Rasmussen DN, Petersen TS, Macias-Perez IM, Pavliv L, Kaelin B, et al. Fewer adverse effects associated with a modified two-bag intravenous acetylcysteine protocol compared to traditional three-bag regimen in paracetamol overdose. Clin Toxicol. 2018:1–7.
Wong A, Gunja N, McNulty R, Graudins A. Analysis of an 8-hour acetylcysteine infusion protocol for repeated supratherapeutic ingestion (RSTI) of paracetamol. Clin Toxicol. 2018;56(3):199–203.
Chiew A, Fountain JS, Graudins A, Isbister GK, Reith D, Buckley NA. Summary statement: new guidelines for the management of paracetamol poisoning in Australia and New Zealand. Med J Aust. 2015;203(5):215–8.
Cook SF, King AD, Chang Y, Murray GJ, Norris HR, Dart RC, et al. Quantification of a biomarker of acetaminophen protein adducts in human serum by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: clinical and animal model applications. J Chromatogr B Analyt Technol Biomed Life Sci. 2015;985:131–41. https://doi.org/10.1016/j.jchromb.2015.01.028.
Curry SC, Padilla-Jones A, Ruha AM, O'Connor AD, Kang AM, Wilkins DG, et al. The relationship between circulating acetaminophen-protein adduct concentrations and alanine aminotransferase activities in patients with and without acetaminophen overdose and toxicity. J Med Toxicol. 2019.
James LP, Chiew A, Abdel-Rahman SM, Letzig L, Graudins A, Day P, et al. Acetaminophen protein adduct formation following low-dose acetaminophen exposure: comparison of immediate-release vs extended-release formulations. Eur J Clin Pharmacol. 2013;69(4):851–7.
Court MH, Zhu Z, Masse G, Duan SX, James LP, Harmatz JS, et al. Race, gender, and genetic polymorphism contribute to variability in acetaminophen pharmacokinetics, metabolism, and protein-adduct concentrations in healthy African-American and European-American volunteers. J Pharmacol Exp Ther. 2017;362(3):431–40.
Heard KJ, Green JL, James LP, Judge BS, Zolot L, Rhyee S, et al. Acetaminophen-cysteine adducts during therapeutic dosing and following overdose. BMC Gastroenterol. 2011;11:20.
Prescott LF. Paracetamol: past, present, and future. Am J Ther. 2000;7(2):143–7.
Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. Br J Clin Pharmacol. 1980;10(Suppl 2):291S–8S.
Wong A, Homer N, Dear JW, Choy KW, Doery J, Graudins A. Paracetamol metabolite concentrations following low risk overdose treated with an abbreviated 12-h versus 20-h acetylcysteine infusion. Clin Toxicol. 2019;57(5):312–7.
Kietzmann T. Metabolic zonation of the liver: the oxygen gradient revisited. Redox Biol. 2017;11:622–30.
Wong A, Nejad C, Gantier M, Choy KW, Doery J, Graudins A. MicroRNA from a 12-h versus 20-h acetylcysteine infusion for paracetamol overdose. Hum Exp Toxicol. 2019;38(6):646–54.
Wong A, Graudins A. Risk prediction of hepatotoxicity in paracetamol poisoning. Clin Toxicol. 2017;55(8):879–92.
Heard K, Green JL, Anderson V, Bucher-Bartelson B, Dart RC. A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration. BMC Pharmacol Toxicol. 2014;15:39.
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Wong, A., Heard, K., Graudins, A. et al. Adducts Post Acetaminophen Overdose Treated with a 12-Hour vs 20-Hour Acetylcysteine Infusion. J. Med. Toxicol. (2020). https://doi.org/10.1007/s13181-020-00757-9