AJP - Regulatory, Integrative and Comparative Physiology, Vol 247, Issue 3 582-R588, Copyright © 1984 by American Physiological Society
Blood-brain barrier transport and brain sequestration of propranolol and lidocaine
W. M. Pardridge, R. Sakiyama and G. Fierer
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.
