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Ontogeny of Small Intestinal Drug Transporters and Metabolizing Enzymes Based on Targeted Quantitative Proteomics

Márton Kiss1, Richard Mbasu1, Johan Nicolaï1

  • 1Department of Pharmacology and Toxicology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands (M.K., F.G.M.R., S.N.d.W.); Development Science (R.M., K.B., A.K., P.C.), and Statistical Sciences and Innovation (N.K.), UCB BioPharma, Slough, United Kingdom; Development Science, UCB BioPharma SRL, Braine-l'Alleud, Belgium (J.N., A.-L.U.); Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Centre, Leiden, The Netherlands (M.G.M.); and Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (R.M.H.W.).

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|September 22, 2021
PubMed

Insights

This study reveals age-related changes in drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in the pediatric small intestine. These findings are crucial for developing precise drug dosing strategies for children.

Area of Science:

  • Pharmacology and Toxicology
  • Pediatric Gastroenterology
  • Proteomics

Background:

  • Oral drug administration is common in children, but knowledge of small intestinal drug-metabolizing enzymes (DMEs) and drug transporters (DTs) protein abundance across pediatric ages is limited.
  • This information gap impedes the development of precise drug dosing regimens for pediatric populations.
  • Understanding the ontogeny of DMEs and DTs is essential for optimizing pediatric pharmacotherapy.

Purpose of the Study:

  • To investigate age-related differences in the protein abundance of key DMEs and DTs in the human jejunum and ileum.
  • To provide a comprehensive dataset on the maturation of these proteins throughout pediatric development.
  • To establish a foundation for improved pharmacokinetic modeling and precision dosing in children.

Main Methods:

  • Targeted quantitative proteomics was employed to analyze surgical leftover intestinal tissues from pediatric and adult jejunum and ileum.
  • Specific DMEs and DTs analyzed include BCRP, MCT1, MDR1, MRP2, MRP3, OATP2B1, OCT1, PEPT1, CYP2C19, CYP3A4, CYP3A5, UGT1A1, UGT1A10, and UGT2B7.
  • Samples from 58 children (8 weeks to 17 years) and 16 adults were analyzed for comparative age-group and continuous age-scale assessments.

Main Results:

  • Significant differences in the abundance of BCRP, MDR1, PEPT1, and UGT1A1 were observed between adult and pediatric ileum.
  • Jejunal BCRP, MRP2, UGT1A1, and CYP3A4 showed higher abundance in adults compared to very young children (0-2 years).
  • Continuous age analysis indicated higher PEPT1 and UGT1A1, and lower MCT1 and UGT2B7 abundance in adult ileum versus pediatric ileum.

Conclusions:

  • This study provides the first detailed ontogeny of small intestinal DMEs and DTs in humans using targeted quantitative proteomics.
  • Significant age- and intestinal location-specific changes in DME and DT abundance were identified.
  • The generated data are vital for constructing accurate physiologically based pharmacokinetic (PBPK) models to support safer and more effective pediatric drug dosing.

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