title: Acetaminophen-cysteine adducts during therapeutic dosing and following overdose.
abstract: BACKGROUND
  Acetaminophen-cysteine adducts (APAP-CYS) are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from non-acetaminophen hepatotoxins have not been well characterized. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose.
  
  
  METHODS
  Samples were collected during three clinical trials in which subjects received 4 g/day of acetaminophen and during an observational study of acetaminophen overdose patients. Trial 1 consisted of non-drinkers who received APAP for 10 days, Trial 2 consisted of moderate drinkers dosed for 10 days and Trial 3 included subjects who chronically abuse alcohol dosed for 5 days. Patients in the observational study were categorized by type of acetaminophen exposure (single or repeated). Serum APAP-CYS was measured using high pressure liquid chromatography with electrochemical detection.
  
  
  RESULTS
  Trial 1 included 144 samples from 24 subjects; Trial 2 included 182 samples from 91 subjects and Trial 3 included 200 samples from 40 subjects. In addition, we collected samples from 19 subjects with acute acetaminophen ingestion, 7 subjects with repeated acetaminophen exposure and 4 subjects who ingested another hepatotoxin. The mean (SD) peak APAP-CYS concentrations for the Trials were: Trial 1- 0.4 (0.20) nmol/ml, Trial 2- 0.1 (0.09) nmol/ml and Trial 3- 0.3 (0.12) nmol/ml. APAP-CYS concentrations varied substantially among the patients with acetaminophen toxicity (0.10 to 27.3 nmol/ml). No subject had detectable APAP-CYS following exposure to a non-acetaminophen hepatotoxin.
  
  
  CONCLUSIONS
  Lower concentrations of APAP-CYS are detectable after exposure to therapeutic doses of acetaminophen and higher concentrations are detected after acute acetaminophen overdose and in patients with acetaminophen toxicity following repeated exposure.
authors.affiliation: Rocky Mountain Poison and Drug Center, Denver Health, Denver, CO, USA. kennon.heard@rmpdc.org
authors.forename: Kennon J
authors.initials: KJ
authors.lastname: Heard
authors.forename: Jody L
authors.initials: JL
authors.lastname: Green
authors.forename: Laura P
authors.initials: LP
authors.lastname: James
authors.forename: Bryan S
authors.initials: BS
authors.lastname: Judge
authors.forename: Liza
authors.initials: L
authors.lastname: Zolot
authors.forename: Sean
authors.initials: S
authors.lastname: Rhyee
authors.forename: Richard C
authors.initials: RC
authors.lastname: Dart
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use* / Q000633:toxicity; D000293:Adolescent; D000328:Adult; D000428:Alcohol Drinking / Q000097:blood; D000437:Alcoholism / Q000097:blood; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis; D002648:Child; D003545:Cysteine / Q000031:analogs & derivatives* / Q000097:blood; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D015415:Biomarkers; D000082:Acetaminophen; C069744:acetaminophen cysteine; D003545:Cysteine