ArticleCPT: pharmacometrics & systems pharmacology2026
Semi-Physiological Population Pharmacokinetic Modeling of Oral and Intravenous Paracetamol to Quantify Presystemic Metabolism and Enterohepatic Recirculation.
Article in CPT: pharmacometrics & systems pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Development of Integrated Parent-Metabolite Pharmacokinetic Model With Apparent Presystemic Metabolism to Characterize the Disposition of Alverine.CPT: pharmacometrics & systems pharmacology · 2026Article
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Authors and funding
11 authors.
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Abstract
Paracetamol (PCM) is extensively metabolized in the liver via glucuronidation, sulfation, and oxidation. Although oral and intravenous PCM are commonly used interchangeably, a comprehensive evaluation of PCM metabolism across both routes is lacking. This study aimed to characterize the full pharmacokinetic (PK) profiles of PCM and its metabolites following oral and intravenous administration, accounting for presystemic and systemic metabolism. Concentrations of PCM, PCM-glucuronide (PCM-GLU), PCM-sulfate (PCM-SUL), PCM-cysteine (PCM-CYS), and PCM-mercapturate (PCM-MER) were pooled from three clinical studies, involving 53 adults with obesity and 16 adults without obesity (18-65 years, 53-198 kg). A semi-physiological population PK model was developed with nonlinear mixed-effects modeling, incorporating intestinal and liver compartments, and enterohepatic recirculation. A semi-physiological PK model incorporating presystemic and systemic hepatic metabolism captured PK of PCM and PCM-SUL following oral and intravenous administration. Intestinal oxidative metabolism for PCM-CYS and PCM-MER and enterohepatic recirculation for PCM-GLU were added to capture their full PK profiles. The estimated fraction of PCM absorbed was 0.745 (95% CI 0.699-0.792), with extensive first-pass metabolism and faster metabolite formation after oral than after intravenous administration. This semi-physiological population PK model identified both hepatic and intestinal presystemic metabolism of PCM, as well as enterohepatic recirculation of PCM-GLU. Oral administration of PCM results in faster metabolite formation than intravenous dosing, mainly for the oxidative metabolites. This modeling approach may support the quantification of presystemic and systemic metabolism, which can be relevant for oral and intravenous dosing of drugs metabolized by multiple pathways.
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