Comparison of lipid-mediated blood-brain-barrier penetrability in neonates and adults

Abstract

The permeability of compounds that penetrate brain capillaries by virtue of their lipoidal solubilities was studied in vivo after a single capillary transit by the intracarotid injection technique. Brain permeabilities of 14C-labeled test isotopes were measured relative to that of tritiated water, a highly diffusible reference substance, with correction for any test isotope remaining in the cerebral vasculature. The brain uptake indices of acetamide, antipyrine, benzyl alcohol, butanol, caffeine, cytosine, diphenyl hydantoin, ethanol, ethylene glycol, heroin, mannitol, methanol, phenobarbital, propylene glycol, thiourea, and urea were measured in ether-anesthetized newborn rabbits. A highly significant correlation (r = 0.86) between brain uptake indices and octanol-saline partition coefficients of these compounds was observed. An almost identical relationship was derived in the adult rat blood-brain barrier where brain uptakes and partition coefficients of some 48 compounds could be correlated (r = 0.86). The similarities in slope-intercept relationships indicate that newborn rabbit and adult rat brain endothelia are functionally similar with respect to lipid-mediated permeability [in contrast to previous studies that have established dramatic differences in selective permeabilities of metabolites transported by saturable, carrier-mediated ("facilitated diffusion") mechanisms]. Permeability-surface area products were also derived; these data confirmed no differences in permeability could be detected between newborn and adult blood-brain-barrier capillaries. A relationship between hydrogen bond number (an alternative indicator of hydrophobic properties( and brain uptake indices derived for the adult rat brain could not be confirmed in the case of the newborn rabbit.