Developmental Expression of Drug Transporters and Conjugating Enzymes Involved in Enterohepatic Recycling: Implication for Pediatric Drug Dosing.
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
19 Aug 2024
19 Aug 2024
Historique:
received:
24
04
2024
accepted:
17
07
2024
medline:
20
8
2024
pubmed:
20
8
2024
entrez:
20
8
2024
Statut:
aheadofprint
Résumé
Around 50% of the drugs used in children have never been tested for safety and efficacy in this vulnerable population. Immature drug elimination pathways can lead to drug toxicity when pediatric doses are determined using empirical methods such as body-surface area or body-weight-normalized adult dosing. In the absence of clinical data, physiologically-based pharmacokinetic (PBPK) modeling has emerged as a useful tool to predict drug pharmacokinetics in children. These models utilize developmental physiological data, including age-dependent differences in the abundance of drug-metabolizing enzymes and transporters (DMET), to mechanistically extrapolate adult pharmacokinetic data to children. The reported abundance data of hepatic DMET proteins in subcellular fractions isolated from frozen tissue are prone to high technical variability. Therefore, we carried out the proteomics-based quantification of hepatic drug transporters and conjugating enzymes in 50 pediatric and 8 adult human hepatocyte samples. Out of the 34 studied proteins, 28 showed a significant increase or decrease with age. While MRP6, OAT7, and SULT1E1 were highest in < 1-year-old samples, the abundance of P-gp and UGT1A4 was negligible in < 1-year-old samples and increased significantly after 1 year of age. Incorporation of the age-dependent abundance data in PBPK models can help improve pediatric dose prediction, leading to safer drug pharmacotherapy in children.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Organisme : >National Institutes of Health (NIH)
ID : R01.HD081299
Informations de copyright
© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.
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