Mind the Gaps: Ontogeny of Human Brain P-gp and Its Impact on Drug Toxicity

Area of Science:

• Neuroscience
• Pharmacology
• Developmental Biology

Background:

• Limited data exists on human brain P-glycoprotein ontogeny in infants and children.
• P-glycoprotein plays a crucial role in drug safety and efficacy.
• Pediatric populations are particularly vulnerable to altered drug responses.

Purpose of the Study:

• To review and synthesize available data on the maturation of human brain P-glycoprotein.
• To identify knowledge gaps in understanding P-glycoprotein development in children.
• To provide guidance on drug extrapolation for pediatric populations.

Main Methods:

• Review of post-mortem human brain samples for transporter expression.
• Analysis of in vivo transporter activity using probe substrates.
• Examination of surrogate marker endpoints and animal model extrapolations.

Main Results:

• Current data suggest human brain P-glycoprotein activity continues to develop postnatally.
• The precise developmental timeframe for P-glycoprotein maturation remains unclear.
• Significant knowledge gaps persist regarding pediatric P-glycoprotein ontogeny.

Conclusions:

• Further research is needed to precisely define the developmental trajectory of brain P-glycoprotein.
• Positron emission tomography and central pharmacodynamic responses are potential future research methods.
• Extrapolation of adult drug data to children under two years requires caution for CNS-active drugs.