Dataset Information

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

ABSTRACT:

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.

Conclusion

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.

SUBMITTER: Mooij MG

PROVIDER: S-EPMC5591809 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Successful Use of [<sup>14</sup>C]Paracetamol Microdosing to Elucidate Developmental Changes in Drug Metabolism.

Mooij Miriam G MG van Duijn Esther E Knibbe Catherijne A J CAJ Allegaert Karel K Windhorst Albert D AD van Rosmalen Joost J Hendrikse N Harry NH Tibboel Dick D Vaes Wouter H J WHJ de Wildt Saskia N SN

Clinical pharmacokinetics 20171001 10

<h4>Background</h4>We previously showed the practical and ethical feasibility of using [<sup>14</sup>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 [<sup>14</sup>C]paracetamol (AAP).<h4>Methods</h4>Infants admitted to the intensive care unit received a single oral [<sup>14</sup>C]AAP microdose while receiving intravenous thera ...[more]

PMID: 28155137

Similar Datasets

Project description:BackgroundAlmonertinib Mesilate Tablets (HS-10296, Hansoh Pharma, Shanghai, China) is a novel and selective third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). A phase I study of almonertinib in patients with non-small cell lung cancer (NSCLC) demonstrated a linear metabolic trend, a good tolerability/safety profile, and preliminary antitumor activity. However, the metabolism, excretion, and substance balance of almonertinib has not been clearly determined. Here, we investigated the pharmacokinetic characteristics and safety profile of almonertinib following a single oral dose (110 mg/50 µCi) in healthy Chinese male participants.MethodsTotal radioactivity (TRA) in whole blood, plasma, urine, and feces was measured by utilizing a liquid scintillation counter to obtain almonertinib substance balance data. The pharmacokinetic parameters of [14C]almonertinib and the parent drug almonertinib in whole blood and plasma were analyzed with noncompartmental analysis in the WinNonlin software (Pharsight Corp). The major metabolites in plasma, urine, and feces were analyzed by high-performance liquid chromatography (HPLC) coupled with an online or offline isotope detector. The safety of the drug was evaluated after administration.ResultsThe safety and tolerability of a single oral dose of 110 mg/50 µCi [14C] almonertinib suspension were good in healthy Chinese male participants. There was no significant abnormality or special adverse reaction. TRA peaked quickly in plasma, with a Tmax of 4.0 h; however, TRA was cleared slowly in vivo, with a mean terminal elimination phase (half-life, T1/2) of up to 863 h. In addition to the parent drug, a total of 26 metabolites in blood, urine, and feces were analyzed. In plasma, parent drug was the major drug-related component, accounting for 69.97% of TRA, and M440 (almonertinib-M2 demethyl product) was the major metabolite, accounting for 5.08% of TRA; in urine, parent drug accounted for 0.48% of the dose administered and HAS-719 was the major metabolite, accounting for 1.20% of the administered dose; in feces, parent drug was about 8.61% of the dose administered and HAS-719 was the major metabolite, accounting for 12.33% of the administered dose, which was followed by M541a/M470a and M617/M575, accounting for 11.8% and 6.76% of the administered dose, respectively.ConclusionsAlmonertinib has a good safety profile, with parent drug as its main circulating component. almonertinib is extensively metabolized in vivo before excretion and is excreted as a parent drug and metabolites mainly via feces.Trial registrationThe trial registration number: CTR20192291.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

Successful Use of [<sup>14</sup>C]Paracetamol Microdosing to Elucidate Developmental Changes in Drug Metabolism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

Successful Use of [<sup>14</sup>C]Paracetamol Microdosing to Elucidate Developmental Changes in Drug Metabolism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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