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Successful Use of [14C]Paracetamol Microdosing to Elucidate Developmental Changes in Drug Metabolism

M. Mooij, Esther van Duijn, C. Knibbe, K. Allegaert, A. Windhorst, J. van Rosmalen, N. Hendrikse, D. Tibboel, Wouter Vaes, S. D. de Wildt

Clinical Pharmacokinetics February 2, 2017 DOI: 10.1007/s40262-017-0508-6 (opens in new tab)

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AI-extracted from the abstract
Characteristics Observational pharmacokinetic study Peer reviewed
Sample size 50
Population Infants and children admitted to the intensive care unit, median age 6 months (range 3 days to 6.9 years)
Dose 3.3 ng/kg (range 2.0-3.5 ng/kg); 64 Bq/kg (range 41-71 Bq/kg)
Topics Microdosing
Key findings Age-related changes in paracetamol metabolism were measurable using a carbon-14-labeled microdose: with increasing age, plasma and urinary glucuronide-to-paracetamol and glucuronide-to-sulfate ratios increased about fourfold, while the sulfate-to-paracetamol ratio decreased. The authors argue that microdosing is an attractive, low-burden approach for studying developmental changes in drug disposition in children.

Abstract

BackgroundWe previously showed the practical and ethical feasibility of using [14C]-microdosing for pharmacokinetic studies in children. We now aimed to show that this approach can be used to elucidate developmental changes in drug metabolism, more specifically, glucuronidation and sulfation, using [14C]paracetamol (AAP).MethodsInfants admitted to the intensive care unit received a single oral [14C]AAP microdose while receiving intravenous therapeutic AAP every 6 h. [14C]AAP pharmacokinetic parameters were estimated. [14C]AAP and metabolites were measured with accelerator mass spectrometry. The plasma area under the concentration-time curve from time zero to infinity and urinary recovery ratios were related to age as surrogate markers of metabolism.ResultsFifty children [median age 6 months (range 3 days–6.9 years)] received a microdose (3.3 [2.0–3.5] ng/kg; 64 [41–71] Bq/kg). Plasma [14C]AAP apparent total clearance was 0.4 (0.1–2.6) L/h/kg, apparent volume of distribution was 1.7 (0.9–8.2) L/kg, and the half-life was 2.8 (1–7) h. With increasing age, plasma and urinary AAP-glu/AAP and AAP-glu/AAP-sul ratios significantly increased by four fold, while the AAP-sul/AAP ratio significantly decreased.ConclusionUsing [14C]labeled microdosing, the effect of age on orally administered AAP metabolism was successfully elucidated in both plasma and urine. With minimal burden and risk, microdosing is attractive to study developmental changes in drug disposition in children.

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Analysis of Serotonin in Caenorhabditis Elegans Subjected to Micro-Dosing with Psilocybin| Iris Publishers Caenorhabditis elegans 2025 Experimental study

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