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


METHODS
Infants 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.


RESULTS
Fifty 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.


CONCLUSIONS
Using [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.
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
Miriam G
MG
Mooij
TNO, Zeist, The Netherlands.
Esther
E
van Duijn
Division of Pharmacology, Faculty of Science, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.|Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands.
Catherijne A J
CAJ
Knibbe
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.|Department of Development and Regeneration, KU Leuven, Louvain, Belgium.
Karel
K
Allegaert
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
Albert D
AD
Windhorst
Department of Biostatistics, Erasmus MC, Rotterdam, The Netherlands.
Joost
J
van Rosmalen
Department of Pharmacy and Clinical Pharmacology, VU University Medical Center, Amsterdam, The Netherlands.
N Harry
NH
Hendrikse
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
Dick
D
Tibboel
TNO, Zeist, The Netherlands.
Wouter H J
WHJ
Vaes
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands. saskia.dewildt@radboudumc.nl.|Department of Pharmacology and Toxicology, Radboud University, PO box 9101, Geert Grooteplein 21, Nijmegen, 6500 HB, The Netherlands. saskia.dewildt@radboudumc.nl.
Saskia N
SN
de Wildt
D000082:Acetaminophen / Q000008:administration & dosage* / Q000378:metabolism*; D000367:Age Factors; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000008:administration & dosage* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male
D018712:Analgesics, Non-Narcotic; D002250:Carbon Radioisotopes; D000082:Acetaminophen; C000615234:Carbon-14
Accelerator Mass Spectrometry; Enteral Feeding Tube; Microdosing Study; Propacetamol; Sulfation