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
The present studies measure the transport of retinol, retinoic acid, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], and 25-hydroxyvitamin D3 [25-(OH)D3] through the rat brain capillary endothelial wall, i.e., the blood-brain barrier (BBB). The vitamin A and D derivatives bind both to albumin and to specific high-affinity binding proteins in plasma. In the presence of physiologic concentrations of plasma proteins, the extraction by brain of all four compounds was 5% or less.
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.
The availability of testosterone and estradiol to Sertoli and prostate cells is dependent upon 1) the permeability properties of the blood-tubular barrier (BTB) of the testis or prostate cell membrane, and 2) sex steroid binding to plasma proteins, such as albumin or testosterone-binding globulin (TeBG). Sex steroid influx into these tissues was studied after in vivo arterial bolus injections of [3H]testosterone or [3H]estradiol in anesthetized rats. Both testosterone and estradiol were readily cleared across the BTB or prostate cell membrane in the absence of plasma proteins and in the presence of human pregnancy serum, in which testosterone or estradiol are 80-95% distributed to TeBG. The extravascular extraction of [3H]TeBG across the BTB or prostate plasma membrane [73 +/- 2% (+/- SE) and 92 +/- 9%, respectively] was significantly greater than extraction of [3H]albumin or other plasma space markers and indicative of a rapid first pass clearance of TeBG by Sertoli or prostate cells. In summary, these studies indicate that 1) testosterone and estradiol are readily cleared by Sertoli and prostate cells; 2) albumin- and TeBG-bound sex steroids represent the major circulating pool of bioavailable hormone for testis or prostate; and 3) the TeBG-sex steroid complex may be nearly completely available for influx through the BTB or prostate plasma membrane.
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