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Published on: September 24, 2017
Barriers to Drug Distribution into the Perinatal and Postnatal Brain
Jean-François Ghersi-Egea1,2, Elodie Saudrais3,4, Nathalie Strazielle3,4,5
1FLUID Team, Lyon Neurosciences Research Center, INSERM U1028 CRNS UMR 5292, Université Claude Bernard Lyon-1, 69008, Lyon, France. jean-francois.ghersi-egea@inserm.fr.
Insights
Drug delivery to the developing brain is critical for neonates and infants. Understanding factors affecting drug bioavailability in the brain is essential for safe and effective pediatric and maternal drug treatments.
Area of Science:
- Neuroscience
- Pharmacology
- Developmental Biology
Background:
- Drug bioavailability to the developing brain is a significant concern for pediatric and maternal populations.
- Central adverse drug reactions pose risks to brain development, potentially causing neurological impairment.
Purpose of the Study:
- To investigate the factors influencing drug bioavailability in the developing brain.
- To assess the impact of developmental changes on drug concentrations in the brain.
- To evaluate the role of blood-brain interfaces and perinatal injuries in drug cerebral penetration.
Main Methods:
- Review of factors affecting cerebral drug bioavailability, including plasma concentration, blood flow, barrier permeability, and transporter activity.
- Analysis of developmental changes in these factors and their impact on drug entry.
- Consideration of the influence of perinatal injuries on blood-brain barrier properties.
Main Results:
- Cerebral drug bioavailability is influenced by multiple dynamic factors that change during development.
- Blood-brain barrier and blood-cerebrospinal fluid barrier exhibit early tight phenotypes.
- Developmental regulation of efflux transporters may enhance neonatal brain drug penetration.
Conclusions:
- Developmental changes significantly alter drug cerebral bioavailability, necessitating careful consideration in pediatric and maternal pharmacotherapy.
- Understanding these mechanisms is crucial for accurate risk assessment of drug treatments in vulnerable populations.
- Perinatal injuries can further modify blood-brain interface properties, impacting drug disposition.
Abstract:
Drug bioavailability to the developing brain is a major concern in the treatment of neonates and infants as well as pregnant and breast-feeding women. Central adverse drug reactions can have dramatic consequences for brain development, leading to major neurological impairment. Factors setting the cerebral bioavailability of drugs include protein-unbound drug concentration in plasma, local cerebral blood flow, permeability across blood-brain interfaces, binding to neural cells, volume of cerebral fluid compartments, and cerebrospinal fluid secretion rate. Most of these factors change during development, which will affect cerebral drug concentrations. Regarding the impact of blood-brain interfaces, the blood-brain barrier located at the cerebral endothelium and the blood-cerebrospinal fluid barrier located at the choroid plexus epithelium both display a tight phenotype early on in embryos. However, the developmental regulation of some multispecific efflux transporters that also limit the entry of numerous drugs into the brain through barrier cells is expected to favor drug penetration in the neonatal brain. Finally, drug cerebral bioavailability is likely to be affected following perinatal injuries that alter blood-brain interface properties. A thorough investigation of these mechanisms is mandatory for a better risk assessment of drug treatments in pregnant or breast-feeding women, and in neonate and pediatric patients.
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