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

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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.

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Acknowledgments

This work was supported in part by a research grant from the National Institute for Diabetes and Digestive and Kidney Diseases (DK81406). Drs. James and Roberts have a pending patent application for a point-of-care test for the measurement of acetaminophen protein adducts. Dr. James also receives salary support from the UAMS Translational Research Institute (grant UL1TR000039) through the NIH National Center for Research Resources and National Center for Advancing Translational Sciences.

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Authors and Affiliations

  1. Department of Pediatrics, University of Arkansas for Medical Sciences (UAMS) and Arkansas Children’s Hospital Research Institute, Little Rock, AR, USA

    Laura P. James, Lynda Letzig & Dean Roberts

  2. Clinical and Experimental Toxicology Unit, Department of Emergency Medicine, Prince of Wales Hospital, Randwick, NSW, Australia

    Angela Chiew

  3. Division of Clinical Pharmacology and Medical Toxicology, Children’s Mercy Hospitals and Clinics, Kansas City, MO, USA

    Susan M. Abdel-Rahman

  4. Southern Clinical School, Monash University, Clayton, VIC, Australia

    Andis Graudins

  5. South Eastern Area Laboratory Services (SEALS Pathology), Prince of Wales Hospital Campus, Randwick, NSW, Australia

    Peter Day

  6. Clinical Pharmacology and Toxicology, Arkansas Children’s Hospital, 3 Children’s Way, Little Rock, AR, 72202, USA

    Laura P. James

Authors
  1. Laura P. James
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  2. Angela Chiew
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  3. Susan M. Abdel-Rahman
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  4. Lynda Letzig
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  5. Andis Graudins
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  6. Peter Day
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  7. Dean Roberts
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Corresponding author

Correspondence to Laura P. James.

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James, L.P., Chiew, A., Abdel-Rahman, S.M. et al. Acetaminophen protein adduct formation following low-dose acetaminophen exposure: comparison of immediate-release vs extended-release formulations. Eur J Clin Pharmacol 69, 851–857 (2013). https://doi.org/10.1007/s00228-012-1410-7

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  • DOI: https://doi.org/10.1007/s00228-012-1410-7

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