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

Overview

Journal Clin Pharmacokinet

Specialty Pharmacology

Date 2017 Feb 4

PMID 28155137

Citations 10

Authors

Miriam G Mooij

Esther van Duijn

Catherijne A J Knibbe

Karel Allegaert

Albert D Windhorst

Joost van Rosmalen

N Harry Hendrikse

Dick Tibboel

Wouter H J Vaes

Saskia N de Wildt

Affiliations

Soon will be listed here.

Abstract

Background: We previously showed the practical and ethical feasibility of using [C]-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 [C]paracetamol (AAP).

Methods: Infants admitted to the intensive care unit received a single oral [C]AAP microdose while receiving intravenous therapeutic AAP every 6 h. [C]AAP pharmacokinetic parameters were estimated. [C]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 [C]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.

Conclusion: Using [C]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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