Increased Blood—Brain Barrier Transport of Protein-Bound Anticonvulsant Drugs in the Newborn

Abstract

The extraction of heroin, caffeine, diphenylhydantoin, and phenobarbital has been measured in the newborn, suckling, and adult brain. Anticonvulsant drugs such as diphenylhydantoin and phenobarbital are bound by plasma protein, and it is generally believed that only the fraction of drug that is free (dialyzable) in vitro is available for transport through the blood-brain barrier in vivo. In both the adult and neonatal rat or rabbit, lipid-mediated transport of free phenytoin occurs. In addition, a fraction of the drug that enters the capillary bound to plasma protein also gains access to the brain. A greater amount of protein-bound drug permeates the newborn brain, and this is ascribed to a longer capillary transit time in the neonate. With regard to phenobarbital, the total (i.e., both free and protein-bound) plasma drug enters the newborn brain. In contrast, no protein-bound phenobarbital permeates the adult brain, and it is only the free drug fraction that gains access to the brain. Since the blood—brain barrier permeability—surface area product for the two anticonvulsants is unchanged in newborn and older animals, the age-related differences in brain uptake of protein-bound drugs can be attributed to developmental changes in cerebral blood flow and capillary transit time. The increased transport of protein-bound drugs in the newborn may cause increased concentrations (i.e., brain:plasma ratios) of these anticonvulsants in the neonatal brain.