ObjectivesRecent 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.
MethodsBumetanide levels in extracellular fluid (ECF) and plasma in the presence and absence of oat3 inhibitor probenecid were monitored using integrated microdialysis.
Key findingsFollowing a bumetanide bolus/continuous infusion of 10mg/kg and 6mg/kg/h, bumetanide was detected in hippocampal ECF at the estimated concentration of 13155ng/ml. Plasma bumetanide levels were approximate to 20mg/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.
ConclusionAlthough 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.