Acetaminophen metabolism revisited using non-targeted analyses: Implications for human biomonitoring

Area of Science:

• Pharmacology and Toxicology
• Biomonitoring and Analytical Chemistry

Background:

• Paracetamol/acetaminophen (APAP) is a widely used analgesic, but its accurate biomonitoring is challenging due to its short half-life.
• Current methods relying on free APAP and phase II conjugates may underestimate exposure.
• Accurate internal exposure assessment is crucial for risk evaluation of APAP's potential health effects.

Purpose of the Study:

• To investigate novel APAP metabolites for improved biomonitoring.
• To address the underestimation of APAP use by standard analytical methods.
• To determine if additional metabolites beyond direct phase II conjugates enhance APAP monitoring.

Main Methods:

• Controlled longitudinal exposure study with male volunteers.
• Non-targeted high-resolution mass spectrometry for metabolite identification.
• Analysis of free APAP, phase II conjugates, and novel thiomethyl metabolites.

Main Results:

• Overlooked APAP metabolites, specifically conjugated thiomethyl metabolites, were identified.
• These novel metabolites exhibit delayed formation and excretion rates.
• The diagnostic sensitivity of thiomethyl metabolites is comparable to current biomarkers, with extended detection windows.

Conclusions:

• Conjugated thiomethyl metabolites offer improved APAP exposure assessment due to delayed excretion.
• Including these metabolites in biomonitoring can decrease the underestimation of APAP use.
• Standard biomonitoring methods solely based on APAP and its phase II metabolites may be inadequate for non-persistent chemicals.