Barriers to Drug Distribution into the Perinatal and Postnatal Brain
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.
KEY WORDSblood-brain barrier cerebrospinal fluid choroid plexus development efflux transporters
Adverse drug reaction
Central nervous system
Acknowledgements and disclosures
This work was funded by ANR-10-IBHU-0003 CESAME grant.
- 1.Agency EM. Report on the survey of all paediatric uses of medicinal products in Europe. 2010 http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/01/WC500101006.pdf.
- 4.Agency EM. Evidence of harm from off-label or unlicensed medicines in children. 2004 http://www.ema.europa.eu/docs/en_GB/document_library/Other/2009/10/WC500004021.pdf.
- 7.Andropoulos DB. Effect of anesthesia on the developing brain: infant and fetus. Fetal Diagn Ther. 2018;43(1):1–11.Google Scholar
- 8.Jain KK. Drug-induced neurological disorders. Hogrefe Publishing; 2011.Google Scholar
- 10.Agency EM. Reflection paper on extrapolation of efficacy and safety in 4 paediatric medicine development. 2016 http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2016/04/WC500204187.pdf.
- 11.Administration UFad. Pediatric Science and Research Activities. https://www.fda.gov/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/ucm106614.htm.
- 12.Agency EM. Needs for paediatric medicines. http://www.ema.europa.eu/ema/indexjsp?curl=pages/regulation/document_listing/document_listing_000096jsp&mid=WC0b01ac0580925b1e.
- 13.Ward RM, Benjamin DK, Jr., Davis JM, Gorman RL, Kauffman R, Kearns GL, et al. The need for pediatric drug development. J Pediatr 2017.Google Scholar
- 17.Sammons HM, Choonara I. Learning lessons from adverse drug reactions in children. Children (Basel). 2016;3(1):1.Google Scholar
- 28.Szmydynger-Chodobska J, Chodobski A, Johanson CE. Postnatal developmental changes in blood flow to choroid plexuses and cerebral cortex of the rat. Am J Phys. 1994;266(5 Pt 2):R1488–92.Google Scholar