title: The effect of organic anion transporter 3 inhibitor probenecid on bumetanide levels in the brain: an integrated in vivo microdialysis study in the rat.
abstract: OBJECTIVE
  Recent data highlight the potential of bumetanide as a treatment for neonatal seizures and autism, as it facilitates the excitatory to inhibitory switch in gamma-aminobutyric acid signalling. This study examines the extent of blood-brain barrier (BBB) permeation of bumetanide, a key determinant of the efficacy of centrally acting drugs. Furthermore, the impact of efflux transporter organic anion transporter 3 (oat3) inhibition on bumetanide pharmacokinetics was investigated.
  
  
  METHODS
  Bumetanide levels in extracellular fluid (ECF) and plasma in the presence and absence of oat3 inhibitor probenecid were monitored using integrated microdialysis.
  
  
  RESULTS
  Following a bumetanide bolus/continuous infusion of 10 mg/kg and 6 mg/kg/h, bumetanide was detected in hippocampal ECF at the estimated concentration of 131 ± 55 ng/ml. Plasma bumetanide levels were ∼20 mg/l at steady state. Coadministration of probenecid resulted in an increase in bumetanide levels in both ECF and plasma, indicating that oat3 inhibition influences the pharmacokinetics of bumetanide primarily in the periphery.
  
  
  CONCLUSIONS
  Although bumetanide reached detectable levels in hippocampal ECF, bumetanide concentration in ECF was low relative to systemic concentration. Oat3 inhibition by probenecid resulted in increased bumetanide concentrations in brain and plasma. As an acute treatment in neonatal seizures, the bumetanide/probenecid combination may hold therapeutic potential.
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Donovan
authors.forename: Fionn E
authors.initials: FE
authors.lastname: O'Brien
authors.forename: Geraldine B
authors.initials: GB
authors.lastname: Boylan
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Griffin
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002034:Bumetanide / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D045604:Extracellular Fluid / Q000378:metabolism*; D018682:GABA Agents / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors*; D011339:Probenecid / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley
chemical_list: D000277:Adjuvants, Pharmaceutic; D018682:GABA Agents; D027361:Organic Anion Transporters; D002034:Bumetanide; D011339:Probenecid
keywords: biopharmaceutics and drug disposition; drug delivery to specific tissues; drug disposition in tissues and whole animals; pharmaceutics and drug delivery; pharmacokinetics and drug disposition