title: Blood-brain barrier damage and brain penetration of antiepileptic drugs: role of serum proteins and brain edema.
abstract: OBJECTIVE
  Increased blood-brain barrier (BBB) permeability is radiologically detectable in regions affected by drug-resistant epileptogenic lesions. Brain penetration of antiepileptic drugs (AEDs) may be affected by BBB damage. We studied the effects of BBB damage on brain distribution of hydrophilic [deoxy-glucose (DOG) and sucrose] and lipophilic (phenytoin and diazepam) molecules. We tested the hypothesis that lipophilic and hydrophilic drug distribution is differentially affected by BBB damage.
  
  
  METHODS
  In vivo BBB disruption (BBBD) was performed in rats by intracarotid injection of hyperosmotic mannitol. Drugs (H3-sucrose, 3H-deoxy-glucose, 14C-phenytoin, and C14-diazepam) or unlabeled phenytoin was measured and correlated to brain water content and protein extravasation. In vitro hippocampal slices were exposed to different osmolarities; drug penetration and water content were assessed by analytic and densitometric methods, respectively.
  
  
  RESULTS
  BBBD resulted in extravasation of serum protein and radiolabeled drugs, but was associated with no significant change in brain water. Large shifts in water content in brain slices in vitro caused a small effect on drug penetration. In both cases, total drug permeability increase was greater for lipophilic than hydrophilic compounds. BBBD reduced the amount of free phenytoin in the brain.
  
  
  CONCLUSIONS
  After BBBD, drug binding to protein is the main controller of total brain drug accumulation. Osmotic BBBD increased serum protein extravasation and reduced free phenytoin brain levels. These results underlie the importance of brain environment and BBB integrity in determining drug distribution to the brain. If confirmed in drug-resistant models, these mechanisms could contribute to drug brain distribution in refractory epilepsies.
authors.affiliation: Department of Neurological Surgery, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Marchi
authors.forename: Giulia
authors.initials: G
authors.lastname: Betto
authors.forename: Vincent
authors.initials: V
authors.lastname: Fazio
authors.forename: Quinyuan
authors.initials: Q
authors.lastname: Fan
authors.forename: Chaitali
authors.initials: C
authors.lastname: Ghosh
authors.forename: Andre
authors.initials: A
authors.lastname: Machado
authors.forename: Damir
authors.initials: D
authors.lastname: Janigro
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism; D001921:Brain / Q000187:drug effects*; D001929:Brain Edema / Q000378:metabolism* / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003847:Deoxyglucose / Q000378:metabolism; D003975:Diazepam / Q000493:pharmacokinetics; D004234:Diuretics, Osmotic / Q000008:administration & dosage; D004563:Electrochemistry / Q000379:methods; D006624:Hippocampus; D066298:In Vitro Techniques; D008297:Male; D008353:Mannitol / Q000008:administration & dosage; D008954:Models, Biological; D010672:Phenytoin / Q000493:pharmacokinetics; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013395:Sucrose / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D000927:Anticonvulsants; D001798:Blood Proteins; D002247:Carbon Isotopes; D004234:Diuretics, Osmotic; D014316:Tritium; D008353:Mannitol; D013395:Sucrose; D010672:Phenytoin; D003847:Deoxyglucose; D003975:Diazepam