Related Experiment Video
Updated: May 16, 2026

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
Assessing the impact of child/adult differences in hepatic first-pass effect on the human kinetic adjustment factor
Mathieu Valcke1, Kannan Krishnan
1Département de Santé Environnementale et Santé au Travail, Université de Montréal, CP 6128, Succursale Centre-Ville, Montréal, QC, Canada H3C 3J7. mathieu.valcke@inspq.qc.ca
Abstract:
The objective of this study was to evaluate the impact of interindividual differences in hepatic first-pass effect (FPE) on the magnitude of the human kinetic adjustment factor (HKAF) for ingested toxicants. This factor aims at replacing a default value of 3.2 used in non-cancer risk assessment. Coupled with Monte Carlo simulations, steady-state equations that account for FPE were used to obtain distributions of arterial blood concentrations (CAss) and rates of metabolism in adults, neonates, infants and toddlers continuously exposed to an oral dose of 1 μg/kg/d of theoretical CYP2E1 and CYP1A2 substrates. For such substrates exhibiting a range of blood:air partition coefficients (Pb: 1-10,000) and hepatic extraction ratios in an average adult (E(ad): 0.01-0.99), HKAFs were computed as the ratio of the 95th percentile of dose metrics for each subpopulation over the 50th percentile value in adults. The reduced hepatic enzyme content in neonates as compared to adults resulted in correspondingly diminished FPE. Consequently, HKAFs greater than 3.2 could be observed, based on CAss only, in the following cases: for some CYP2E1 substrates with E(ad) ≤ 0.3, in neonates (max.: 6.3); and for some CYP1A2 substrates with E(ad) ≤ 0.1 and 0.7, in, respectively, neonates and infants (max.: 28.3). Overall, this study pointed out the importance of accounting for child/adult differences in FPE when determining the HKAF for oral exposure.
Related Concept Videos
Effect of Hepatic Disease on Pharmacokinetics: Pathophysiologic Assessment and Liver Function Test
Effect of Hepatic Disease on Pharmacokinetics: Active Drug, Metabolite and Fraction of Metabolized Drug
Pharmacokinetics in Pediatric Patients: Drug Metabolism
Effect of Hepatic Disease on Pharmacokinetics: Dose Adjustments Due to Hepatic Impairment
Effect of Hepatic Disease on Pharmacokinetics: Drug Dosing and Hepatic Blood Flow
Pharmacokinetics in Pediatric Patients: Overview and Drug Absorption

