Circadian Rhythm-Related Modulation of Acetaminophen Oxidation Exposure at Term: A PBPK Simulation Study

Background: Acetaminophen (APAP) is widely used in pregnancy, and its oxidative metabolite N-acetyl-p-benzoquinone imine (NAPQI) may contribute to hepatotoxicity. Whether dosing time affects APAP oxidative metabolism during pregnancy remains undetermined. Methods: In a pregnancy physiologically based pharmacokinetic (PBPK) model of APAP, circadian rhythms in CYP2E1, hepatic blood flow (HBF), and glomerular filtration rate (GFR) were described by cosine functions. Maternal APAP and NAPQI-related exposure was simulated after a single 1000 mg oral dose at four dosing times at 40 weeks of gestation. Counterfactual analyses in which each rhythm was switched off quantified its contribution to the difference in the 20:00/08:00 exposure ratio relative to the no-rhythm reference. Rhythm amplitude, peak phase, and interindividual variability were also examined. Results: APAP exposure varied little with dosing time, with 20:00/08:00 ratios of 0.92 for AUC0–48h and 0.96 for Cmax. NAPQI-related exposure was highest at 20:00 and lowest at 08:00, with AUC0–48h and Cmax ratios of 2.42 and 3.52; virtual population simulations showed the same direction (median ratios, 2.52 and 3.51). Rhythm-removal comparisons showed that CYP2E1 had the largest conditional contribution (91.00% for AUC0–48h and 89.69% for Cmax, respectively), while HBF contributions were smaller and GFR contributed less than 1%. Increasing CYP2E1 amplitude widened the exposure change, whereas shifting its peak phase to 08:00 or 12:00 reversed the effect direction. Conclusions: These hypothesis-generating computational predictions identify biological timing as a determinant of modeled oxidative exposure at term. Clinical evaluation is needed before they can inform dosing decisions.