1. ¹Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, USA
2. ²Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
3. ³Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
4. ⁴Department of Pediatrics, Schools of Medicine, Pharmacy, and Pharmaceutical Sciences, University of California at San Diego, San Diego, California, USA
5. ⁵Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
6. ⁶Department of Pediatrics, University of Missouri–Kansas City, Kansas City, Missouri, USA
7. ⁷Department of Pharmacology, University of Missouri–Kansas City, Kansas City, Missouri, USA
8. ⁸Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA
9. ⁹Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio, USA
10. ¹⁰Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA
11. ¹¹Rainbow Children's Hospital, Cleveland, Ohio, USA
12. ¹²Department of Pediatrics, University of Louisville, Louisville, Kentucky, USA
13. ¹³Kosair Children's Hospital, Louisville, Kentucky, USA
14. ¹⁴Bethesda, Marayland, USA

Correspondence: LP James, (jameslaurap@uams.edu)

Received 11 July 2008; Accepted 26 August 2008; Published online 15 October 2008.

Abstract

Acetaminophen protein adducts (APAP adducts) were quantified in 157 adolescents and children presenting at eight pediatric hospitals with the chief complaint of APAP overdose. Two of the patients required liver transplantation, whereas all the others recovered spontaneously. Peak APAP adducts correlated with peak hepatic transaminase values, time-to-treatment with N-acetylcysteine (NAC), and risk determination per the Rumack–Matthews nomogram. A population pharmacokinetic analysis (NONMEM) was performed with post hoc empiric Bayesian estimates determined for the elimination rate constants (k_e), elimination half-lives (t_1/2), and maximum concentration of adducts (C_max) of the subjects. The mean (SD)k_e and half-life were 0.486 0.084 days^-1 and 1.47 0.30 days, respectively, and the C_max was 1.2 (2.92) nmol/ml serum. The model-derived, predicted adduct value at 48 h (Adduct 48) correlated with adductC_max, adduct T_max, Rumack–Matthews risk determination, peak aspartate aminotransferase (AST), and peak alanine aminotransferase (ALT). The pharmacokinetics and clinical correlates of APAP adducts in pediatric and adolescent patients with APAP overdose support the need for a further examination of the role of APAP adducts as clinically relevant and specific biomarkers of APAP toxicity.