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Biomedical subjects

S Urien

Publications and source records attributed to S Urien.

At least 91 records · Page 5Linked to original sources
PubMed1989

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. The fraction of drug uptaked by tissue (tissue available fraction) was always dramatically greater than the in vitro free drug fraction, and this was interpreted as an enhanced in vivo drug dissociation from the binding protein. The fraction of drug uptake by salivary gland was closer to the in vitro free fraction than the fraction of drug uptake by brain tissue. The addition of palmitic acid to HSA induced parallel changes in the in vitro free fraction of warfarin and in the brain tissue or salivary gland extraction of warfarin. These data indicate that a part of protein-bound warfarin (as determined in vitro) is available for tissue extraction via an enhanced in vivo dissociation of the drug-protein complex in the tissue microcirculation. The in vitro data were fitted to a saturable model of binding whereas the in vivo data could satisfactorily fit a model dealing with a nonsaturable model of binding, and this is probably the result of the several-fold increase in the in vivo dissociation constant.

Animals↗
PubMed1988

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. Indapamide was bound to erythrocytes via a saturable process with a high affinity (K = 385/mM and N = 57 microM for an hematocrit value of 0.48), and erythrocytes were the main binding component in blood (more than 80% of indapamide was associated to erythrocytes in blood). The binding to serum proteins affected indapamide distribution in blood, and alpha 1-acid glycoprotein was shown to be the more effective protein in decreasing the amount of indapamide associated to erythrocytes.

Blood Platelets↗
PubMed1988

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 +/- 3.4%, P less than .001), decreased in patients with hepatic insufficiency (72.3 +/- 5.9%, P less than .001) and unchanged in patients with renal insufficiency (77.7 +/- 2.8%) as compared with controls (78.2 +/- 3.1%). A multivariate analysis indicated that these changes were mainly related to concomitant changes in AAG concentration (that explained 63% of intersubject variability in bound/free binding ratio), and to a lesser extent to HSA (that explained only 4% of the variability in the binding). These data show that the free fraction of the acidic drug indapamide in serum is affected by pathologic conditions in which changes in AAG concentration occur and that, unexpectedly, HSA plays a negligible role in the binding.

Adolescent↗
PubMed1988

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 (88.8%) and it was unchanged in patients with renal insufficiency (92.8%) as compared to controls (92.7%). Multivariate analysis indicated that the changes were mainly related to concomitant changes in AAG concentration, which could account for 57% of intersubject variability in the bound/free ratio, and to a lesser extent in HSA, which accounted for only 4% of the variability in the binding. The data show that the free fraction of the basic drug tertatolol in serum is affected by pathological conditions that cause changes in AAG concentration.

Adolescent↗
PubMed1988

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 = 0.03) but different Bmax values. Two groups of arteries could be distinguished, large-sized with high Bmax (aorta, 149 fmol/mg, SD = 4; intrapulmonary, 134 fmol/mg, SD = 4) and medium-sized with lower Bmax (mesenteric, 67 fmol/mg, SD = 2; internal carotid, 50 fmol/mg, SD = 2; renal artery, 29 fmol/mg, SD = 2). The Kd values were similar to those previously reported, but the Bmax value on aorta SMC was higher than usually reported with other DHPs, showing that isradipine was a high full antagonist of calcium channel. Our results also suggest that the increase in arterial compliance induced by DHPs will probably be more important on large-sized arteries than on medium-sized arteries because of higher DHP binding.

Animals↗
PubMed1988

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. The free dialyzable drug fraction was inversely related to the protein concentration. Despite this degree of binding, no significant reduction in the brain extraction of the drug was observed in the presence of HSA, lipoprotein, or erythrocytes. Only AAG reduced the brain transport of this drug in a ratio related to the protein concentration. However, the rat brain extraction was higher than expected from the in vitro measurement of the dialyzable fraction. These data indicate that the amount of circulating imipramine available for penetration in brain exceeds widely the dialyzable fraction of the drug as measured in vitro.

Algorithms↗
PubMed1988

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. In the liver, high-affinity binding sites for serum albumin have been demonstrated, and they would explain the high extraction by liver of endogenous and exogenous compounds. However, these experiments measure the unidirectional transfer of a drug from the vascular to the extravascular space in non-steady-state conditions. Hence, in steady-state conditions, the free drug hypothesis cannot be ruled out because it is supported by numerous pharmacokinetic studies.

Animals↗
PubMed1988

Comparative binding of two closely related dihydropyridines (isradipine and darodipine) to serum proteins and erythrocytes.

The binding of the two drugs isradipine and darodipine, chemically related to dihydropyridines and potent calcium channel blockers, was studied in vitro to isolated plasma proteins, erythrocytes and human serum. The two drugs were strongly bound to serum proteins (up to 97%), mainly to human serum albumin (HSA), alpha 1-glycoprotein (AAG) and lipoproteins (VLDL, LDL and HDL). Their bindings to AAG were saturable with high affinity constants (isradipine 498,000 M-1, darodipine = 155,000 M-1; n = 1). The binding of these drugs to HSA, VLDL and HDL was unsaturable, but it was saturable on LDL. In blood the drugs partitioned in erythrocytes, 16% for isradipine and 14.8% for darodipine.

Binding, Competitive↗
PubMed1988

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. However, although the ratio of active and toxic doses in animals can be extrapolated to man, the approach is limited and the NSAID needs to be assessed in a clinical setting as early as possible. In France, a national survey system has reported a wide range of adverse effects related to NSAIDs and shown important differences between compounds. Overdosage may be one of the factors responsible for toxicity, therefore pharmacokinetic evaluation is useful. In some disease states e.g. rheumatoid arthritis, there is a higher possibility of saturation pharmacokinetics with some drugs. Other pharmacokinetic parameters of interest are half-life, functions limiting activity, and hepatotoxicity. Furthermore, different pharmacokinetic parameters are required for different forms of disease. In acute states, the NSAID should have a short half-life and low protein binding and vice versa in chronic states. An important goal is to develop more selective NSAIDs regarding mechanisms of action or distribution into diseased tissues.

Animals↗
PubMed1988

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. The distribution of Cy A between blood cells and plasma was ascribed to a nonlinear saturable model in the two groups. According to our results we have simulated the blood-plasma concentration ratio of Cy A as a function of plasma Cy A concentration and hematocrit.

Adolescent↗
PubMed1988

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. 2. In other words, drug effects are not unique or isolated, because drug distribution is not selective. Thus, considering a drug with a given liposolubility, its quantitative distribution in the body may be predicted in taking into account the physico-chemical properties of the compound and the blood flows and the lipid contents of the different tissues and organs it will reach. 3. This paper attempts to show that plasma binding can influence the tissue distribution of drugs and may be applied to the minimization of toxic effects by decreasing the amounts of drug reaching the relevant tissues. 4. The value of an early determination of drug binding in human blood will be emphasized. This is justified by the fact that tissue distribution of drugs does not vary greatly between species whereas plasma binding may show important inter-species differences. Thus different plasma binding in humans may lead to large variations in tissue distribution as compared with experimental animals.

Animals↗
PubMed1987

Binding in vitro of pipequaline (45319 RP) onto plasma proteins and blood cells in man.

Serum binding of pipequaline, a new anxiolytic drug, was studied in vitro by equilibrium dialysis. The percent binding in serum is high, 96.3%, and remains constant within the range of therapeutic concentrations. Investigations performed on isolated proteins with a wide range of concentrations showed one site with a high affinity constant (Ka = 450,000 M-1) for alpha 1-acid glycoprotein and two sites with a lower affinity constant (Ka = 58,000 M-1) for human serum albumin. Binding to lipoproteins was saturable, with an affinity constant of 22,000 less than or equal to Ka less than or equal to 35,000 M-1. Over the range of therapeutic concentrations, the ratio of pipequaline concentrations in serum and red blood cells remained constant (14.4%) and was shown to be dependent on the free fraction of pipequaline in serum.

Adult↗
PubMed1987

Effect of erythrocytes and plasma protein binding on the transport of progabide and SL 75102 through the rat blood-brain barrier.

Brain extraction of two antiepileptic compounds, progabide and its acid metabolite, SL 75102, was investigated using the carotid injection technique in the rat. The extent to which drug binding to plasma proteins could inhibit the brain extraction was measured. Equilibrium dialysis at 4 degrees showed that both drugs were highly bound to human serum proteins, mainly to serum albumin. Progabide is also bound to red blood cells and to lipoproteins. The free dialyzable drug fraction was inversely related to the protein concentration. Similarly, the brain extraction of the drugs in the presence of either albumin, or red blood cells for progabide was inversely related to their respective concentrations. However, the rat brain extraction of both drugs was higher than expected from the in vitro measurement of dialyzable fraction. Furthermore, despite a significant degree of progabide binding to lipoproteins, no significant reduction in the brain extraction of the drug was observed. These data indicate that the amount of circulating progabide or SL 75102 available for penetration in a peripheral tissue such as brain exceeds the dialyzable fraction of drug. However, the in vivo exchangeable drug fraction still parallels the dialyzable fraction, except if the drug is lipoprotein-bound.

Biological Transport, Active↗
PubMed1987

Binding of two anthranilic acid derivatives to human albumin, erythrocytes, and lipoproteins: evidence for glafenic acid high affinity binding.

The binding of two anthranilic acid derivatives, glafenic and floctafenic acids, to human erythrocytes and plasma proteins has been investigated in vitro by equilibrium dialysis. Despite their close chemical structures it was shown that the binding of the two compounds to serum albumin, lipoproteins, and erythrocytes was dramatically different both in quality and quantity. Using various techniques including fluorometry and circular dichroism, it was shown that glafenic acid binds to the human serum albumin (HSA) warfarin/azapropazone site and that floctafenic acid binds to both warfarin/azapropazone and benzodiazepine sites. Glafenic acid is strongly bound to HSA with n = 1, k = 2.4 X 10(6) liters/mol and to erythrocytes with N = 12.4 mumol/liter, K = 1.7 X 10(6) liters/mol. Floctafenic acid is bound with a weaker affinity to HSA, n = 2, k = 0.3 X 10(6) liters/mol and to erythrocytes, N = 2900 mumol/liter and K = 0.007 X 10(6) liters/mol.

Analgesics↗
PubMed1987

Comparative study of bepridil and nicardipine action on respiration and calcium transport in mitochondria.

Effects of the calcium antagonists bepridil and nicardipine on mitochondrial functions were studied and their effects on respiratory control and calcium fluxes were compared. Results show that bepridil and nicardipine similarly increase Ca2+ intracellular movements, but that intramitochondrial Ca2+ storage is increased by bepridil whereas it is decreased by nicardipine. The in vivo significance of these findings remain to be determined. The effect of bepridil might be related to an enhancement of mitochondrial ATPase activity whereas nicardipine would act on mitochondria by a different mechanism.

Adenosine Triphosphatases↗
PubMed1987

Effect of the binding of isradipine and darodipine to different plasma proteins on their transfer through the rat blood-brain barrier. Drug binding to lipoproteins does not limit the transfer of drug.

Brain extraction of two calcium channel antagonists, isradipine (PN 200-110) and darodipine (PY 108-068) was investigated using the carotid injection technique in rats. An inhibitor effect of binding to plasma proteins on the brain extraction was also investigated. Equilibrium dialysis at 37 degrees C showed that both drugs were highly bound to human serum proteins, including albumin, alpha-1 acid glycoprotein and lipoproteins. The free dialyzable drug fraction was inversely related to the protein concentration. The brain extraction of the drugs in the presence of either albumin or alpha-1 acid glycoprotein was inversely related to the protein concentrations in the presence of either albumin or alpha-1 acid glycoprotein, but it was higher than expected from the in vitro measurement of the dialyzable fraction. Despite a significant degree of binding to lipoproteins, no significant reduction in the brain extraction of the drugs was observed, regardless of the class or the concentration of lipoproteins. These data indicate that the amount of circulating darodipine or isradipine available for entry in a peripheral tissue such as brain exceeds the dialyzable fraction of drug. However, the in vivo exchangeable drug fraction still parallels the dialyzable fraction, except if the drug is lipoprotein bound.

Animals↗
PubMed1987

Progabide and SL 75102 binding to plasma proteins and red blood cells in humans.

The binding of progabide and its metabolite, SL 75102, was studied in vitro by equilibrium dialysis. The progabide binding percentage in serum remained constant (approximately equal to 96%) over a wide range of concentrations. Binding of progabide was characterized by one class of sites to human serum albumin (HSA) (n = 3.8 +/- 0.2; K = 2.5 X 10(4) M-1). The binding to alpha 1 acid glycoprotein (AAG) was also shown to be saturable with n = 1.7 +/- 0.2 and K = 3.1 X 10(4) M-1. Progabide was bound to a lesser extent to red blood cells (RBC), lipoproteins and gamma-globulins. The SL 75102 binding percentage in serum remained constant (approximately equal to 98%), over a range of concentrations exceeding therapeutic levels. SL 75102 showed two saturable classes of binding sites to HSA: the first one with n1 = 0.8 +/- 0.1 and K1 = 10(6) M-1 and the second one with n2 = 7.9 +/- 0.2 and K2 = 8.1 X 10(3) M-1. The binding to AAG was also shown to be saturable with n = 0.7 +/- 0.1 and K = 1.6 X 10(4) M-1. SL 75102 was bound to a lesser extent to RBC, lipoproteins and gamma-globulins. The binding parameters were used to calculate the distribution of progabide and SL 75102 among the components in whole blood over the therapeutic range. The calculations showed that serum albumin was the major binding component for the parent drug and its metabolite.

Anticonvulsants↗