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

Abstract

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.

Investigation on the Influx Transport Mechanism of Pentazocine at the Blood-Brain Barrier in Rats Using the Carotid Injection Technique.

“…7) This observation is in agreement with the effect of pH for cationic drugs such as lidocaine, mepyramine or propranolol using in vivo carotid injection technique. 14,15) The concentration-dependent uptake of PTZ at pH 5.5 showed the participation of a saturable uptake process (Fig. 3).…”

“…Thus, PTZ is transported into the brain predominantly by a carrier-mediated mechanism. It was reported that the saturable BBB influx transport of cationic drugs showed an apparent low-affinity system for propranolol (K t ϭ9.8 mM) 14) or mepyramine (K t ϭ4.4 mM), 15) using the in vivo carotid injection technique. When the uptake of PTZ was measured by the in situ brain perfusion technique, the apparent influx transport of PTZ was saturable, with a K m value of 2.9 mM.…”

“…However, the process has another possibility that the other low affinity carrier-mediated transport system remains as suggested in our previous perfusion study. 7) PTZ transport at the BBB was inhibited by several cationic drugs such as lidocaine, 14) propranolol, 14) mepyramine, [15][16][17] diphenhydramine 18) and amantadine, 19) which are transported into the brain via the specific carrier system for cationic drugs ( Table 1). The inhibitory effect on the influx transport was especially shown in lidocaine, propranolol or diphenhydramine by both the in vivo carotid injection and in situ brain perfusion techniques.…”

Tracer kinetic model of blood-brain barrier transport of plasma protein-bound ligands. Empiric testing of the free hormone hypothesis.

“…With regard to the test compounds, the extraction at 15 s is not significantly different from the initial extraction. Owing to active sequestration mechanisms in the brain for the steroid hormones and for propranolol, the half-life of ligand distribution in brain after a pulse injection is 4-6 min (14,15). Therefore, the ligand efflux to blood in 15 s is <5%.…”

A Double-Radionuclide Autoradiographic Method Using N-Isopropyl-Iodoamphetamine for Sequential Measurements of Local Cerebral Blood Flow

“…(1982) found that brain ex traction of IMP was decreased from a value of 92 to 74% when the arterial blood pH was lowered from 7.35 to 7.10. Pardridge's group proposed that this may be a pH effect (Pardridge and Fierer, 1985) since amphetamine(s) as well as other lipophilic basic amines are transported through the blood brain barrier substantially more slowly at lower pH (Pardridge and Connor, 1973;Pardridge et al, 1984). Therefore, it appears that LCBF measure ments with IMP as tracer should be further vali dated under conditions associating high CBF with low arterial blood pH, e.g., during respiratory aci dosis.…”