Transport of Propranolol and Lidocaine through the Rat Blood-Brain Barrier. PRIMARY ROLE OF GLOBULIN-BOUND DRUG

Abstract

A B S T R A C T Basic lipophilic drugs such as propranolol and lidocaine are strongly bound by a1-acid glycoprotein, also called orosomucoid. Although the liver is known to rapidly clear plasma protein-bound propranolol or lidocaine, it is generally regarded that peripheral tissues, such as brain or heart, are only exposed to the small fraction of drug that is free or dialyzable in vitro. The "free drug" hypothesis is subjected to direct empiric testing in the present studies using human sera and an in vivo rat brain paradigm.Serum from 27 human subjects (normal individuals, newborns, or patients with either metastatic cancer or rheumatoid arthritis) were found to have up to a sevenfold variation in orosomucoid concentrations. The free propranolol or lidocaine as determined in vitro by equilibrium dialysis at 370C varied inversely with the orosomucoid concentration. Similarly the rate of transport of propranolol or lidocaine through the blood-brain barrier (BBB) was inversely related to the existing serum concentration of orosomucoid. However, the inhibition of rat brain extraction of drug by orosomucoid in vivo was only about one-fifth of that predicted by free drug measurements in vitro. This large discrepancy suggested orosomucoid-bound drug was readily available for transport into brain in vivo.Studies using purified human orosomucoid in the rat brain extraction assay also showed that orosomucoidbound propranolol or lidocaine is readily transported through the BBB. Conversely, albumin-bound propranolol or lidocaine was not transported through the BBB. The studies using albumin provide evidence that

Effects of albumin and .ALPHA.1-acid glycoprotein on the transport of imipramine and desipramine through the blood-brain barrier in rats.

“…For instance, Weisiger et al 13,16) presented the albumin receptor-mediated transport concept to account for the transport of fatty acid, sulfobromophthalein and bilirubin into the liver, and Forker and Luxon14, 15) suggested the presence of albumin-mediated transport in the liver for rose bengal and taurocholate. Subsequently, we also found an albumin-mediated hepatic uptake of warfarin using the multiple indicator dilution method.31) Pardridge et al 18,19) suggested a "free intermediate model" to explain the transport of many substances such as steroid hormone and l-propranolol (PL) into the brain. Recent in vivo studied showed that the transit time of albumin through the liver and brain is not delayed compared with that of an extracellular marker such as sucrose.32,33) In addition, in vitro studies using liver plasma membranes34) and brain microvessels33) could not detect any specific binding to albumin and failed to support the albumin receptor-mediated transport concept in either liver or brain.…”

Mechanism of Brain Targeting by Dexibuprofen Prodrugs Modified with Ethanolamine-Related Structures

“…These results, together with the observation that transport was dependent on pH but independent of sodium and membrane potential ( Figures 5A and 5B), suggest that I and II share a common H +/ OC transporter with pyrilamine. 31 To further explore the fate of prodrugs after they are taken up into BCECs, we examined their transendothelial transport in a BCEC-AC coculture model of the BBB. This model relies on transwell culture inserts to create 'contact through feet' interface for interactions between the two cell types.…”

The P-glycoprotein inhibitor quinidine decreases the threshold for bupivacaine-induced, but not lidocaine-induced, convulsions in rats

“…Pardridge et al 2 showed that influx of lidocaine to the brain is not restricted by the blood brain barrier. Pajeva et al 24 also reported that lidocaine does not interact with phospholipids constructing tumour cells expressing P-gp.…”

“…Previous studies have shown that influx of globulinbound as well as free lidocaine into the brain is not prevented by the blood brain barrier. 2 However, the blood brain barrier permeability of bupivacaine, a widely used long-acting local anesthetic with high lipid solubility and more than 90% protein binding, has not been examined.…”