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Developmental patterns in human blood-brain barrier and blood-cerebrospinal fluid barrier ABC drug transporter

L F M Verscheijden1, A C van Hattem1, J C L M Pertijs1

  • 1Department of Pharmacology and Toxicology, Radboud University Medical Center, Institutes for Molecular Life and Health Sciences, Nijmegen, The Netherlands.

Histochemistry and Cell Biology
|May 26, 2020
PubMed

Insights

Drug dosing in children requires careful consideration due to immature brain barriers. This study reveals age-dependent changes in key ABC transporters, P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), impacting drug disposition in the developing brain.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Developmental Biology

Background:

  • Drug dosage extrapolation from adults to children is risky due to immature blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) function.
  • Age-related variations in membrane transporters can significantly alter drug distribution in the brain.
  • Limited human data exists on the age-dependent expression of brain transporters.

Purpose of the Study:

  • To investigate the age-dependent variation in the expression and localization of key ABC transporters (Pgp, BCRP, MRP1/2/4/5) in the human brain.
  • To understand how the maturation of the BBB and BCSFB affects drug disposition across different developmental stages.

Main Methods:

  • Immunohistochemical analysis of post-mortem brain cortical and ventricular tissue from fetuses, neonates, children, and adults.
  • Quantification of staining intensity and localization for Pgp, BCRP, MRP1, MRP2, MRP4, and MRP5.

Main Results:

  • Pgp and BCRP expression in the cortical BBB increased with age.
  • MRP1 and MRP2 showed higher staining intensity in fetuses, neonates, and children compared to adults.
  • BCRP was not detected in the BCSFB, while Pgp, MRP1, and MRP2 were stable across age groups.

Conclusions:

  • Human BBB and BCSFB ABC membrane transporters exhibit distinct age-dependent maturation patterns.
  • These findings highlight the importance of considering developmental changes in transporter expression for pediatric drug dosing.
  • Transporter-specific maturation influences drug disposition in the developing brain.

Keywords:
ATP-binding cassette transportersBlood–brain barrierBlood–cerebrospinal fluid barrierBrain pharmacokineticsChildFetus

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