European Journal of Clinical Pharmacology

, Volume 69, Issue 4, pp 851–857

Acetaminophen protein adduct formation following low-dose acetaminophen exposure: comparison of immediate-release vs extended-release formulations

  • Laura P. James
  • Angela Chiew
  • Susan M. Abdel-Rahman
  • Lynda Letzig
  • Andis Graudins
  • Peter Day
  • Dean Roberts
Pharmacokinetics and Disposition

DOI: 10.1007/s00228-012-1410-7

Cite this article as:
James, L.P., Chiew, A., Abdel-Rahman, S.M. et al. Eur J Clin Pharmacol (2013) 69: 851. doi:10.1007/s00228-012-1410-7

Abstract

Purpose

Acetaminophen (APAP) protein adducts are a biomarker of APAP metabolism, reflecting oxidation of APAP and generation of the reactive metabolite N-acetyl-p-benzoquinone imine. High levels of adducts correspond to liver toxicity in patients with APAP-related acute liver failure. Adduct formation following low-dose exposure to APAP has not been well studied. APAP protein adducts were measured in blood samples collected from fasted individuals who participated in a crossover study of APAP (80 mg/kg) comparing extended release (ER) and immediate release (IR) formulations.

Methods

Adducts were quantified in all postdose blood samples using a validated high-performance liquid chromatography electrochemical detection (HPLC-EC) assay.

Results

Comparison of pharmacokinetic parameters for adducts did not reveal significant differences between ER and IR formulations, with one exception. Formation rates for adducts were faster for IR than the ER formulation (0.420 ± 0.157 vs. 0.203 ± 0.080 1/h), respectively. Maximum plasma concentrations (Cmax) of adducts for IR and ER were 0.108 (±0.020) and 0.100 (±0.028) nmol/ml serum, respectively, and were two orders of magnitude lower than adduct levels previously reported in adults with acute liver failure secondary to APAP.

Conclusions

APAP protein adducts are rapidly formed following nontoxic ingestion of APAP at levels significantly lower than those associated with acute liver failure.

Keywords

Biomarker Acetaminophen Hepatotoxicity Adducts Metabolism Glutathione 

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Laura P. James
    • 1
    • 6
  • Angela Chiew
    • 2
  • Susan M. Abdel-Rahman
    • 3
  • Lynda Letzig
    • 1
  • Andis Graudins
    • 4
  • Peter Day
    • 5
  • Dean Roberts
    • 1
  1. 1.Department of PediatricsUniversity of Arkansas for Medical Sciences (UAMS) and Arkansas Children’s Hospital Research InstituteLittle RockUSA
  2. 2.Clinical and Experimental Toxicology Unit, Department of Emergency MedicinePrince of Wales HospitalRandwickAustralia
  3. 3.Division of Clinical Pharmacology and Medical ToxicologyChildren’s Mercy Hospitals and ClinicsKansas CityUSA
  4. 4.Southern Clinical SchoolMonash UniversityClaytonAustralia
  5. 5.South Eastern Area Laboratory Services (SEALS Pathology)Prince of Wales Hospital CampusRandwickAustralia
  6. 6.Clinical Pharmacology and ToxicologyArkansas Children’s HospitalLittle RockUSA

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