Paracetamol (acetaminophen) protein adduct concentrations during therapeutic dosing

Abstract

Background: Paracetamol protein adducts (PPA) are a biomarker of paracetamol exposure. PPA are quantified as paracetamol-cysteine (APAP-CYS), and concentrations above 1.1 μmol l(-1) have been suggested as a marker of paracetamol-induced hepatotoxicity. However, there is little information on the range of concentrations observed during prolonged therapeutic dosing.

Aim: The aim of the present study was to describe the concentration of PPA in the serum of subjects taking therapeutic doses of paracetamol for at least 16 days.

Methods: Preplanned secondary aim of a prospective randomized controlled (placebo vs. 4g day(-1) paracetamol) trial. We measured subjects' serum PPA concentrations every 3 days for a minimum of 16 days. We also measured concentrations on study days 1-3 and 16-25 in subsets of patients. PPA were quantified as APAP-CYS after gel filtration and protein digestion using liquid chromatography/mass spectrometry.

Results: Ninety per cent of subjects had detectable PPA after five doses. Median APAP-CYS concentrations in paracetamol-treated subjects increased to a plateau of 0.1 μmol l(-1) on day 7, where they remained. The highest concentration measured was 1.1 μmol l(-1) and two subjects never had detectable PPA levels. PPA were detected in the serum of 78% of subjects 9 days after their final dose.

Conclusions: PPA are detectable in the vast majority of subjects taking therapeutic doses of paracetamol. While most have concentrations well below the threshold associated with hepatotoxicity, concentrations may approach 1.1 μmol l(-1) in rare cases. Adducts are detectable after a few doses and can persist for over a week after dosing is stopped.

Keywords: APAP-CYS; paracetamol; protein adducts.

Figure 1

Serum paracetamol–cysteine (APAP‐CYS) concentrations of subjects administered 4 g day^–1 of paracetamol during the main study period. The line in each figure represents the median value; the box includes the 25th–75th percentile; the ‘whiskers’ include the 10–90th percentile and the dots represent values outside the 10th–90th percentile

Figure 2

Serum paracetamol–cysteine (APAP‐CYS) concentrations during the extended dosing period (days 17–40) in subjects administered 4 g day^–1 paracetamol during the study. The line in each figure represents the median value; the box includes the 25th–75th percentile; the ‘whiskers’ include the 10th–90th percentile and the dots represent values outside the 10th–90th percentile. The number of subjects for each day were: day 19, n = 47; day 22, n = 47; day 25, n = 25; day 28, n = 17; day 31, n = 13; day 34, n = 6; day 37, n = 5; and day 40, n = 2

Figure 3

Serum paracetamol–cysteine (APAP‐CYS) concentrations in subjects during the first 4 days of receiving 4 g day^–1 paracetamol. The line in each figure represents the median value; the box includes the 25th–75th percentile; the ‘whiskers’ include the 10th–90th percentile and the dots represent values outside the 10th–90th percentile

Figure 4

Serum paracetamol–cysteine (APAP‐CYS) concentrations in subjects during the resolution phase administration of 4 g day^–1 paracetamol for 16 days. Subjects did not take paracetamol during this phase of the study. Day 0 of the resolution phase was day 16 of the baseline study. The line in each figure represents the median value; the box includes the 25th–75th percentile; the ‘whiskers’ include the 10th–90th percentile and the dots represent values outside the 10th–90th percentile

Figure 5

Correlation of serum alanine aminotransferase (ALT) with serum paracetamol–cysteine (APAP‐CYS) in subjects taking 4 g day^–1 paracetamol. Samples were obtained every 3 days for days 4–16