In vivo evidence for carrier-mediated brain uptake of a new 2-amino-2-oxazoline (COR3224) via the purine transport system in rat.

We studied the brain uptake of a new 2-amino-2-oxazolamines derivative (COR3224) in the rat by means of the rapid intracarotid injection technique described by Oldendorf. The brain uptake index (BUI) of labelled COR3224 decreased progressively from 10% to 5% when concentrations of unlabelled compound were increased. The effect of various compounds indicated that COR3224 is transported into the brain by the purine carrier.

A re-evaluation of the HSA-piroxicam interaction.

Piroxicam binding to HSA was studied using equilibrium dialysis and fluorescence methods. It was shown that this drug, like its analogs isoxicam and tenoxicam, binds to the apazone locus (site I area) and to a lesser extent to the diazepam site (site II). The piroxicam binding to HSA can be modulated by various specific ligands--apazone, warfarin, diazepam, ibuprofen--and these drug interactions have to be considered not only as potential displacement from the HSA binding sites but also in terms of induced allosteric effects.

Assessment of cyclosporine A interactions with human plasma lipoproteins in vitro and in vivo in the rat.

The interaction of cyclosporine A (cyclosporine) with human plasma lipoproteins has been investigated by combining in vitro and in vivo methods. Binding parameters were derived in vitro from an erythrocyte partitioning method, and provided reliable Ka (product of the number of binding sites by the association constant) estimates: high-density lipoprotein, 2.21 +/- 0.

How chronically administered valproate increases chlordiazepoxide transfer through the blood-brain barrier.

Sodium valproate (VPA) is a drug widely used in the treatment of epileptics often in association with benzodiazepines. Recent animal studies have shown that the addition of valproate increases diazepam levels in the cortex and the cerebellum (Hariton et al, 1985). The aim of our study was to determine the effect of VPA on the transfer of benzodiazepines through the blood-brain barrier.

Differences in the serum binding determinants of isradipine and darodipine--consequences for serum protein binding in various diseases.

1. Serum protein binding of isradipine and darodipine, and serum concentrations of alpha 1-acid glycoprotein (AAG), albumin (HSA) and non-esterified fatty acids (NEFA) were measured in three groups of patients, I: healthy subjects (n = 20); II: patients with inflammatory disorders (n = 15) and III: patients with hepatic insufficiency (n = 17). 2.

Pipequaline transport from blood to brain and liver: role of plasma protein-bound drug.

Brain uptake of pipequaline (45319 RP) has been studied in-vivo after a single capillary transit by intracarotid injection to rats. Pipequaline is extensively bound to plasma proteins: i.e.

Pharmacological profile of binedaline, a new antidepressant drug.

The interactions of binedaline (binodaline), a new antidepressant drug, and its main metabolites with neurotransmitter receptors and monoamine uptake sites were studied. In receptor binding assays, binedaline was compared to amitriptyline, imipramine, maprotiline and mianserin. Unlike these drugs binedaline did not show any significant affinity for an alpha adrenergic, muscarinic cholinergic, histamine H1 or serotonin2 (5-HT2) receptors.

Evidence for isoxicam binding to site I as a primary site and to site II as a secondary site of human serum albumin.

Isoxicam binding to HSA was studied using equilibrium dialysis and fluorescence methods. It was shown that this drug binds to or near site I (warfarin or azapropazone site) and to site II (the diazepam site) as a secondary site, although it is generally considered that their respective drug structural requirements are often exclusive. The binding parameters were calculated with different mathematical models; a site oriented model with or without fixing the number of binding sites as integer values and a stoichiometric model.

Effect of alpha-1-acid glycoprotein, albumin and palmitic acid on the brain and salivary gland extraction of warfarin in rats.

The effect of plasma protein binding of warfarin on its transfer into the brain and salivary gland was investigated using alpha-1-acid glycoprotein and human serum albumin (HSA) in combination or not with palmitic acid. The tissue extraction of [14C] warfarin relative to [3H]water was determined by intracarotid injection technique in male Wistar rats. The tissue extraction of warfarin varied inversely with the concentration of added serum protein, (HSA and alpha-1-acid glycoprotein), and addition of palmitic acid to HSA diminished the extraction.

Blood distribution of tenoxicam in humans: a particular HSA drug interaction.

Blood binding of tenoxicam was studied in vitro by equilibrium dialysis. Isolated human plasma proteins and blood cells were checked, and the distribution of the bound form was then calculated. The results showed that tenoxicam is mainly bound to HSA and that binding percentages are not different when measured in plasma (98.

In vitro studies on the blood distribution of almitrine.

Blood binding of almitrine, a highly lipophilic drug, was investigated in vitro. [3H]-Almitrine was incubated in a serum pool and isolated protein and lipoprotein fractions. The investigations were performed by using ultracentrifugation and another method which measures the uptake by proteins from glass beads coated with almitrine.

Binding of indapamide to serum proteins and erythrocytes.

The binding of indapamide to isolated serum proteins and erythrocytes was studied in order to understand its blood distribution. In serum, indapamide was mainly bound to alpha 1-acid glycoprotein with a high affinity (K = 73.4/mM), and to albumin and lipoproteins.

Effects of the binding of imipramine to erythrocytes and plasma proteins on its transport through the rat blood-brain barrier.

Brain extraction of a tricyclic antidepressant, imipramine, was investigated using the carotid injection technique in the rat. The extent to which drug binding to plasma proteins and erythrocytes could inhibit the brain extraction was measured. Equilibrium dialysis showed that imipramine is highly bound to human serum albumin (HSA), alpha 1-acid glycoprotein (AAG), lipoproteins, and erythrocytes.

Serum binding of indapamide in health and disease: primary role of alpha 1-acid glycoprotein.

The serum concentrations of alpha-1-acid glycoprotein (AAG), albumin (HSA), and non-esterified fatty acids (NEFA), and the serum binding of indapamide were measured in four groups of individuals: control (healthy) subjects (N = 24), patients with inflammatory syndrome (N = 28), with hepatic (N = 20) and renal (N = 27) insufficiency. Indapamide serum binding was increased in patients with inflammatory syndrome (82.2 +/- 3.

Binding of [3H]isradipine (PN 200-110) on smooth muscle cell membranes from different bovine arteries.

The binding of [3H]isradipine [( 3H]PN 200-110), a new dihydropyridine (DHP) calcium blocker on smooth muscle cell (SMC) membranes from different bovine arteries was saturable with comparable high affinities but different binding site densities (Bmax). The data were fitted to a model that provided a common estimation for the dissociation constant (Kd = 0.46 nM, SD = 0.

Plasma and tissue binding as determinants of drug body distribution. Possible applications to toxicological studies.

1. Drugs are distributed through all body tissues via blood circulation. Consequently, most drugs rarely elicit one specific pharmacological effect but more generally have several, in different tissues.

Distribution of cyclosporin A between blood cells and plasma of cardiac and renal transplant recipients.

The relationship between blood cells and plasma concentrations of cyclosporin A (Cy A) determined by radioimmunoassay, was investigated in 12 heart and 12 kidney transplant recipients. The decision between a linear and nonlinear model was made according to a standardized residuals plot. We observed high blood cells-plasma concentration ratios in the two groups, indicating a high affinity of Cy A for blood cells.

Blood binding and tissue uptake of drugs. Recent advances and perspectives.

The free drug hypothesis, which states that only the unbound moiety of drug in blood is available for tissue diffusion, is discussed according to recent investigations. In some experimental conditions, it must be assumed that part of the protein-bound drug in plasma is extracted during a single passage through the organ studied. The mechanisms underlying these observations are not unequivocal and remain hypothetical.

Pharmacological criteria for risk-benefit evaluation of NSAIDs.

Evaluation of new non-steroidal anti-inflammatory drugs (NSAIDs) must compare efficacy and toxicity with existing compounds. Real progress involves maintaining effectiveness while decreasing toxicity. It is relatively easy to assess the effects of NSAIDs in animal models, and to determine gastrointestinal toxicity.

Variation in serum binding of tertatolol mediated by disease-induced modification of alpha-acid glycoprotein concentration.

The serum concentrations of alpha 1-acid glycoprotein (AAG), albumin (HSA) and non-esterified fatty acids, and the serum binding of tertatolol were measured in four groups of individuals: healthy control subjects (n = 24), and patients with inflammation (n = 28), and hepatic (n = 20) and renal (n = 27) insufficiency. Serum binding of tertatolol was increased in patients with inflammation (94.6%), decreased in patients with hepatic insufficiency (88.