Comments to the Article Wu Y, Völler S, Goulooze SC, et al. A Novel Maturation Equation for Hepatic Clearance Across Preterm, Term Neonates, Children, and Adults: Application to Paracetamol and Its Metabolite. J Clin Pharmacol. 2025;65(12):1829‐1843. doi: 10.1002/jcph.70080. PMID: 40910464; PMCID: PMC12649303

A recent article in this journal by Wu et al presented a comprehensive model for the maturation of paracetamol clearance from birth to adulthood using pooled plasma and urinary data of the parent drug and its metabolites from 298 subjects. The modeling showed that the oxidative bioactivation to hepatotoxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) is generally around 10% of the total clearance. We would like to comment on the authors' discussion on the formation of NAPQI, which highlights once again the main role of CYP2E1 in the oxidative bioactivation metabolism of paracetamol. CYP2E1 was demonstrated as a primary catalyst in the bioactivation of paracetamol, referring only to the paper of Johnsrud et al, that describes only the developmental phase of CYP2E1 in man.