Blood-brain barrier transport and brain sequestration of propranolol and lidocaine.

Lipophilic amine drugs such as propranolol and lidocaine are actively sequestered by tissues via saturable cytoplasmic binding systems. The present studies were designed to characterize the kinetics of drug transport and sequestration in rat brain in vivo by using the carotid injection technique. Both propranolol and lidocaine are sequestered by brain, and the half time (t 1/2) of clearance of the drugs from brain to blood is 6-7 min. The t 1/2 of propranolol association and dissociation reactions with the brain sequestration system are 0.38 +/- 0.03 and 1.33 +/- 0.20 min, respectively. The blood-brain barrier transport of propranolol and lidocaine is inhibited by acid pH, and drug transport is mediated by a low-affinity, high-capacity saturable transport system [propranolol half-saturation constant (Km) = 9.8 +/- 1.2 mM, maximal rate of saturable transport (Vmax) = 5.7 +/- 0.7 mumol X min-1 X g-1, and nonsaturable transport constant (KD) = 0.061 +/- 0.012 ml X min-1 X g-1). These studies indicate that in addition to cerebral blood flow, the distribution of lipophilic amines in brain is a function of plasma pH and of the activity of brain sequestration systems. The latter may represent high-capacity cytoplasmic drug-binding proteins that normally bind endogenous ligands in brain.