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Acetaminophen‐Associated Hepatic Injury: Evaluation of Acetaminophen Protein Adducts in Children and Adolescents With Acetaminophen Overdose
Author(s) -
James LP,
Capparelli EV,
Simpson PM,
Letzig L,
Roberts D,
Hinson JA,
Kearns GL,
Blumer JL,
Sullivan JE
Publication year - 2008
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2008.190
Subject(s) - acetaminophen , alanine transaminase , acetaminophen overdose , adduct , medicine , population , pharmacokinetics , aspartate transaminase , liver transplantation , liver injury , nomogram , gastroenterology , chemistry , anesthesia , acetylcysteine , transplantation , biochemistry , enzyme , alkaline phosphatase , environmental health , organic chemistry , antioxidant
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 adduct C 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. Clinical Pharmacology & Therapeutics (2008); 84 , 6, 684–690 doi: 10.1038/clpt.2008.190