Abstract
Background: A major concern for clinicians in prescribing medications to pregnant women and neonates is the possibility that drugs might have damaging effects, particularly on long-term brain development. Current understanding of drug permeability at placental and blood-brain barriers during development is poor. In adults, ABC transporters limit many drugs from entering the brain; however, little is known about their function during development. Methods: The transfer of clinically relevant doses of paracetamol (acetaminophen), digoxin and cimetidine into the brain and cerebrospinal fluid (CSF) was estimated using radiolabelled drugs in Sprague Dawley rats at three developmental stages: E19, P4 and adult. Drugs were applied intraperitoneally either acutely or following chronic exposure (for five days). Entry into brain, CSF and transfer across the placenta was measured and compared to three markers (L-glucose, sucrose, glycerol) that cross barriers by "passive diffusion". The expression of ABC transporters in the brain, choroid plexus and placenta was estimated using RT-qPCR. Results: All three drugs entered the developing brain and CSF in higher amounts than the adult brain and CSF. Comparisons with "passive" permeability markers suggested that this might be due to age-related differences in the functional capacity of ABC-efflux mechanisms. In adult animals, chronic treatment reduced digoxin (12% to 5%, p<0.01) and paracetamol (30% to 21%, p<0.05) entry compared to acute treatment, with the decrease in digoxin entry correlating with up-regulation of efflux transporter abcb1a (PGP). In fetal and newborn animals, no gene up-regulation or transfer decreases were observed. Instead, chronic paracetamol treatment resulted in increased transfer into the fetal brain (66% to 104%, p<0.001). Conclusions: These results suggest that the developing brain may be more at risk from acute drug exposure than the adult brain due to reduced efflux capacity and at greater risk from chronic treatment due to a lack of efflux mechanism regulatory capacity.
Highlights
The mechanisms that prevent or limit entry of drugs and toxins into the adult brain are reasonably well known
Results from in vivo drug studies were compared with gene expression data to establish which ATP-binding cassette (ABC) transporters changed their expression following chronic exposure, in order to see if they correlated with observed changes in drug entry results
For gene-based studies (RT-qPCR), genes will be listed with common protein names in brackets, e.g. abcc1 (MRP1), whereas for protein-based experimentation, the protein name will be listed with associated gene in brackets, e.g. MRP1
Summary
The mechanisms that prevent or limit entry of drugs and toxins into the adult brain are reasonably well known. Members of the ATP-binding cassette (ABC) transporter family, known to be located in the various brain barrier interfaces (Roberts et al, 2008; Saidijam et al, 2018; Strazielle & Ghersi-Egea, 2015), are major contributors to this protection. They are the main reason why it has proved so difficult to develop new drugs for neurological and neuropsychiatric conditions. Conclusions: These results suggest that the developing brain may be more at risk from acute drug exposure than the adult brain due to reduced efflux capacity and at greater risk from chronic treatment
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