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Controlled Clinical Trial
. 2011 Mar 14:11:20.
doi: 10.1186/1471-230X-11-20.

Acetaminophen-cysteine adducts during therapeutic dosing and following overdose

Kennon J Heard  1 , Jody L Green, Laura P James, Bryan S Judge, Liza Zolot, Sean Rhyee, Richard C Dart
Affiliations
Controlled Clinical Trial

Acetaminophen-cysteine adducts during therapeutic dosing and following overdose

Kennon J Heard et al. BMC Gastroenterol. .

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.

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Figures

Figure 1
Figure 1
Serum APAP-CYS concentrations for subjects in three trials. Subjects received 4 g/day of acetaminophen for 10 days (Trials 1 and 2) or 5 days (trial 3) starting at day 1. Bars represent the 10-90th percentile for each study and values outside that range are shown as '•'.
Figure 2
Figure 2
Peak APAP-CYS concentration by peak ALT during three trials where subjects were administered 4 g/day of acetaminophen.
Figure 3
Figure 3
Serum APAP-CYS concentrations and ALT activity for seven patients who received acetylcysteine treatment within 8 hours of their acute acetaminophen overdose. Clinical characteristics of the cases are shown in Table 2. Note that the scale of the axes are different for subject SH-04 to reflect in the range of values for this subject.
Figure 4
Figure 4
Serum APAP-CYS concentrations and ALT activity for three patients who received acetylcysteine treatment more than 8 hours after their acute acetaminophen overdose. Clinical characteristics of the cases are shown in Table 2. Note that the scale of the axes are not the same for all subjects to reflect the differences in the range of values.
Figure 5
Figure 5
Serum APAP-CYS concentrations and ALT activity for three patients who were treated with acetylcysteine for hepatic injury following repeated supratherapeutic ingestion of acetaminophen. Clinical characteristics of the cases are shown in Table 2. Note that the scale of the axes are not the same for all subjects to reflect the differences in the range of values.
Figure 6
Figure 6
Peak APAP-CYS concentrations plotted by peak ALT for patients treated within 8 hours of acute overdose, for patients treated more than 8 hours after acute overdose and patients treated for repeated supratherapeutic ingestion (RSTI).
See this image and copyright information in PMC

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