Abstracts

Rationale: Loss of blood-brain barrier (BBB) permeability is commonly associated with vasogenic edema. Brain regions affected by malformation of cortical development and epileptogenic lesions are characterized by radiologically detectable loss of water homeostasis. Under these circumstances, the brain penetration of anti epileptic drugs (AED) may be affected by the disorganization of the blood-brain interface and subsequential inadequate or uneven perivascular and interstitial water distribution. We have tested the hypothesis that BBB opening and changes in brain water content alter the brain distribution of the hydrophylic radiolabel compounds 3H-Deoxy-Glucose (DOG) and 3H-Sucrose and of the lipophylic AED 14C-Phenytoin and 14C-Phenobarbital.Methods: In vivo: BBB disruption (BBBD) was performed in rats by intracarotid injection of a 1.4 M mannitol solution. A cocktail of 14C and 3H radiolabelled drugs (1µCi/drug) was injected 2-3 minutes after BBBD. The brain was then dissected out, blood collected and radioactivity measured. BBB opening was evaluated by intravascular infusion of Evans Blue. In vitro: Hippocampal slices were incubated for 30’ in oxygenated artificial CSF-derived solutions at different osmolarities (250-390 mosm/L). Slices were then incubated (5’ to 10’) with radiolabel drugs. Changes in the brain water content were evaluated by a densimetric assay. Results: In vivo, a hemispheric increase in BBB permeability to Evans Blue was observed in cortical and hippocampal areas. Opening of the BBB resulted in increased brain penetration of all the tracers tested compared to the contralateral hemisphere or to control brain (no BBBD). This increase was greater for the lipophylic (20 ± 2 and 30 ± 5 fold for phenytoin and diazepam respectively) compared to the hydrophilic compounds (13 ± 2 and 10 ± 2 fold for glucose and sucrose respectively, p<0.05). In vitro: Incubation with solutions with different osmolarity induced changes in brain slices water content (80 ± 12 %). Water content lead to an augmented uptake in the brain of hydrophilic and lipophylic compounds; the latter increase was, as observed in vivo, more dramatic. Conclusions: We provide pilot data on drug brain distribution in the presence of damaged BBB and changes brain water content. Brain penetration of lipophylic AED was favored by increased water content and BBB permeability. This effect can be explained in vitro by an enhanced drug convection transport due to water flow into the slice and in vivo by the loss of BBB protection, both favoring the partition of the lipophylic drug with the lipophylic parenchyma. Acknowledgments: This work was Supported by NIH-NS43284, NIH-HL51614, NIH-NS46513, NIH-NS049514 and NIH-NS38195