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Biomedical subjects

R Zini

Publications and source records attributed to R Zini.

At least 55 records · Page 3Linked to original sources
PubMed1990

Disease-induced variations in plasma protein levels. Implications for drug dosage regimens (Part I).

Many diseases appear to lead to a decrease of drug plasma binding due either to hypoalbuminaemia or to a modification of albumin structure. In other diseases, the binding of a drug may increase due to elevated concentrations of alpha 1-acid glycoprotein or lipoproteins. However that may be, the free fraction of a drug may vary in different pathologies. But an increase or decrease of the drug free fraction does not automatically mean an increase or decrease of the free drug concentration. Whatever the drug, a variation in the volume of distribution more or less proportional to the variation in the plasma free fraction can be expected. With respect to the clearance, the problem is much more complex and depends on the hepatic extraction ratio of drug. If the extraction is related to the free fraction (fu) of drug, a variation in fu will lead to a variation in the total drug concentration but no variation in the free drug concentration and no change in the pharmacological effect. If the extraction of a drug is dependent on hepatic flow, a variation in fu will lead to a change in the free drug concentration (with no change in the total drug concentration) and hence changes in the pharmacological effect. The aim of this article is to review the literature concerning disease-induced variations in plasma protein levels during the past 10 years. Finally, possible implications for drug dosage regimens are discussed generally from examples studies in the literature.

Animals↗
PubMed1990

Disease-induced variations in plasma protein levels. Implications for drug dosage regimens (Part II).

Part I of this article, which appeared in the previous issue of the Journal, discussed the implications of variations in plasma protein levels in a number of diseases: hepatic and renal disease, acute myocardial infarction, burns, cancer, diabetes mellitus, hyperlipidaemia and inflammatory diseases. In Part II the authors continue their review with a further range of disease states, and consider their import for drug dosages.

Animals↗
PubMed1990

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 +/- 0.48; low-density lipoprotein, 1.23 +/- 0.12; and very low-density lipoprotein, 0.53 +/- 015 liters/g, showing that high-density lipoprotein was the major carrier of plasma cyclosporine. The effects of cyclosporine binding to lipoproteins were investigated in vivo by the intracarotid injection technique of Oldendorf in the rat. The brain extraction of cyclosporine was related inversely to the lipoprotein concentration in the injected solution, allowing estimation of nKa in vivo: high-density lipoprotein, 2.25 +/- 0.59; low-density lipoprotein, 0.62 +/- 0.13; and very low-density lipoprotein, 0.57 +/- 0.14 liters/g. This showed that brain uptake occurred from the free drug pool and possibly from a small part of the originally lipoprotein-bound pool of cyclosporine, at least for low-density lipoprotein-bound cyclosporine. These results allow the calculation of an index of the unbound plasma cyclosporine fraction.

Animals↗
PubMed1989

Tetracycline and erythromycin distribution in pathological lungs of humans and rat.

Tetracycline and erythromycin concentrate highly in pulmonary tissues in humans as well as in the rat. Their binding to the lung, whatever the species and the pathological state, is weak. Their intrapulmonary concentrations could be explained by a passive diffusion which depends on the pH variation between the intra- and extratissue compartments, the percentage of un-ionized form present, and their liposolubility. The importance of retention of tetracycline and erythromycin by plasma proteins is demonstrated by the decrease of their pulmonary index of penetration (IP, the intra- and extratissue concentrations ratio). The IP values are, respectively, 1.09 and 1.23 for tetracycline and erythromycin. These concentrations are in excess of their minimal inhibitory concentrations for bacteria responsible for pneumopathies. The lung homogenate binding of these antibiotics is weak (5% for erythromycin and 33% for tetracycline), corresponding to a nonsaturable binding to three main subcellular fractions (nucleus, mitochondria, and cytosol). Tetracycline has the same penetration in healthy or cancerous human lungs, whereas erythromycin presents a decreased IP in cancerous tissue. However, the binding of these antibiotics to healthy or cancerous lung homogenates is similar. So, the structure of cancerous cells is solely responsible for this modification of erythromycin penetration. The intrapulmonary concentration of tetracycline is increased in rat lungs infected by Legionella pneumophila. This modification is due to a great bacteria retention. In contrast, erythromycin possesses the same IP in healthy and infected rat lungs.

Animals↗
PubMed1989

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. human serum albumin (HSA), alpha-1-acid glycoprotein (AAG), lipoproteins and blood cells, mainly erythrocytes. The dialysable drug fraction as measured in-vitro by equilibrium dialysis at 37 degrees C, was inversely related to the concentration of binding component. Similarly, the brain uptake of pipequaline was inversely related to the protein concentration of the injected solution. However, the measured brain uptake of pipequaline was higher than those predicted by in-vitro measurements of dialysable drug for all proteins and erythrocytes, except HSA. These results show that a fraction of bound pipequaline as measured in-vitro is available for transport through the blood brain barrier. HSA-bound pipequaline is an exception as it is restricted to the vascular space. Pipequaline was totally cleared by the liver through a single passage.

Adult↗
PubMed1989

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. Binedaline and desmethylbinedaline were potent inhibitors of the uptake of norepinephrine in synaptosomes from rat cerebral cortex (Ki = 25 and 29 nM, respectively). Binedaline also inhibited 5-HT uptake with a weak affinity (Ki = 847 nM) but was inactive as an inhibitor of dopamine uptake in synaptosomes from rat striatum (Ki greater than 2 microM). No specific binding was found using [3H]binedaline. After 2 weeks of daily administration of binedaline (20 mg/kg i.p.), the number of beta adrenergic recognition sites labeled with [3H]CGP 12177 remained constant in rat forebrain, as did 5-HT2 receptors and benzodiazepine receptors. In contrast a prolonged treatment with maprotiline (20 mg/kg i.p.) increased the apparent Kd value of [3H]CGP 12177 by 43% and the apparent maximal binding value of [3H]RO 15-1788 by 20% as compared to control. Our results indicate that binedaline is comparable to a tricyclic antidepressant drug in inhibiting the norepinephrine uptake but, however, it is devoid of affinity for neurotransmitter receptors. This probably explains why this drug does not induce the classical side effects of tricyclic antidepressant drugs. These results also suggest that a reduction in beta adrenergic, 5-HT2 or benzodiazepine receptors is not always related to an antidepressant chronic treatment.

Aged↗
PubMed1988

Cefazolin serum protein binding and its inhibition by bilirubin, fatty acids and other drugs.

This paper describes the protein binding of cefazolin to human serum and to human serum albumin (HSA) using equilibrium dialysis. The drug is exclusively bound to HSA with a moderate affinity, Ka = 16,600 +/- 1600 M-1, and one saturable binding site, n = 0.73 +/- 0.02. Moreover cefazolin shows a dose-dependent binding leading a possible increase of the free fraction (when its total concentration increases). This antibiotic is displaced by free fatty acids (FFA) and bilirubin. Cefazolin binding to human serum and human serum albumin (HSA) was studied in presence of acidic drugs. At low concentrations clofibric acid and phenylbutazone both exhibiting high affinity for HSA displace strongly cefazolin. Valproic and salicylic acids, sulfamethoxazole, cefoperazone which have approximately the same affinity as cefazolin, must be used at higher concentrations to displace this antibiotic. A particular phenomenon was observed with cefazolin on HSA when associated with furosemide. A low concentration (5-25 microM) of this drug induces a positive cooperativity of binding between cefazolin and HSA. But at a molar ratio of furosemide to albumin greater than one, such cooperative interaction disappears and a competitive inhibition of cefazolin binding occurs. For all drugs studied, a competitive inhibition was found except for tryptophan. Finally, it is concluded that cefazolin shares the warfarin binding site on HSA.

Bilirubin↗
PubMed1988

Study of deutero-isotopomer-induced inhibition of caffeine and phenobarbitone binding to human serum albumin.

The present study of inhibition provides confirmation to previously observed deuterium isotope effects on in vitro caffeine and phenobarbitone binding to human serum albumin (HSA). Addition of either 3,7(C(2H)3)2 or 1,3,7(C(2H)3)3 caffeine induces a 50% loss in both the extent of binding and binding parameters of the unlabelled analog, understandably so in view of the stronger individual HSA binding of the two labelled isotopomers. As concerns caffeine displacement from its HSA sites, we show phenobarbitone and its 5-pentadeuterophenyl analog are equally potent inhibitors of caffeine binding, though their individual HSA binding profiles differ. As for HSA binding interactions between phenobarbitone isotopomers, a 50% decrease in unlabelled phenobarbitone extent of binding is observed in the presence of its 5-pentadeuterophenyl analog. Our results favor the hypothesis of differing binding sites for each isotopomer.

Binding Sites↗
PubMed1988

Study of isotope effects on protein binding by gas chromatography/mass spectrometry of theophylline-phenobarbitone and 2H, 13C, 15N isotopomers.

We describe a comparative study of human serum albumin (HSA) binding by equilibrium dialysis (pH 7.4, 37 degrees C, 3 h) for two groups of isotopic analogues: theophylline and 1-C(2H3)theophylline; unlabelled, 5(ethyl(2H5],-5(phenyl(2H5] and 1,3-15N;2-13C-phenobarbitone. Bound and free drug fractions are quantified by combined gas chromatography/mass spectrometry. In three instances, protein binding parameters are greatly affected by isotopic substitution, namely for: theophylline and 1-C(2H3)theophylline with isotope effects on total binding site concentration (N), affinity constant (Ka) and extent of HSA binding (%) respectively, equal to: NL/NH = 0.51; KaL/KaH = 1.78; %L/%H = 0.96 (L (light) and H (heavy) represent the unlabelled and labelled analogue respectively); phenobarbitone/-5-(phenyl(2H5]phenobarbitone, NL/NH = 1.72; KaL/KaH = 0.56; %L/%H = 1.26; phenobarbitone/1,3-15N;2-13C phenobarbitone, NL/NH = 2.95; KaL/KaH = 0.44; %L/%H = 1.32, together with a change from one (saturable) to two (saturable + non-saturable) families of albumin binding sites in the latter case. Contrasting with these data, no HSA binding isotope effect was observed on phenobarbitone C5 ethyl deuteration.

Carbon Isotopes↗
PubMed1988

Cicletanine binding to human plasma proteins and erythrocytes, a particular HSA-drug interaction.

The binding of cicletanine to human serum, isolated proteins and red blood cells was studied in vitro by equilibrium dialysis. Our results show this drug is highly bound to serum (97.3%) at therapeutic levels. No saturation to the binding sites was seen. Human serum albumin was shown to mainly responsible for this binding (93.5%) with a saturable process characterized by one binding site with a moderate affinity (K = 75800 M-1) and a non saturable process with a low total affinity (nK = 6400 M-1). Like many basic lipophilic drugs, cicletanine showed a saturable binding to alpha-1-acid glycoprotein with one site and a moderate affinity (K = 38,800 M-1). Its binding to lipoproteins and red blood cells was weak and non saturable. Over the range of therapeutic concentrations, the unbound fraction in blood remains constant (3.6%). Moreover, interactions were studied using bilirubin and non esterified fatty acids at pathological concentrations and these endogenous compounds did not alter cicletanine binding human serum or to human serum albumin likewise cicletanine shared the diazepam-site on HSA but no inhibition could take place between cicletanine and the drugs sharing the same binding site in serum at therapeutic levels.

Anti-Arrhythmia Agents↗
PubMed1987

Binding studies of macrolides, lincosamides and streptogramins to Streptococcus G group using [3H]-erythromycin.

Parameters of [3H]-erythromycin binding to Streptococcus are determined in vivo using both equilibrium and kinetic methods. This binding is saturable, reversible and independent of energetic systems. Whatever the methods used, the binding parameters are identical as 14 nM for the dissociation constant of the complex erythromycin-Streptococcus and a density of binding sites of 11,865 molecules/cell. Other macrolides, streptogramins and lincosamides competitively displaced bound [3H]-erythromycin suggesting that these compounds share common binding sites on the bacteria. In parallel, the MIC values of these antibiotics against Streptococcus are determined by agar dilution method in Mueller-Hinton medium with 5% of horse blood in order to compare the binding and microbiological parameters. A strong correlation (n = 0.863) has been found between the corresponding inhibition constants and MIC values. Such binding studies could be used in conjunction with microbiological assays for primary screening of active analogous or other compounds with interfere with [3H]-erythromycin binding to the bacteria.

Anti-Bacterial Agents↗
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

Study of deuterium isotope effects on protein binding by gas chromatography/mass spectrometry. Caffeine and deuterated isotopomers.

A study of the binding to human serum albumin (HSA) of caffeine and its deuterated isotopomers, 1-C2H3-,3-C2H3-, 1,7-(C2H3)2-, 3,7-(C2H3)2- and 1,3,7-(C2H3)3-caffeine, was performed by equilibrium dialysis. Free and bound fractions were measured by gas chromatography/mass spectrometry. Important and significant (Fischer and Student tests) isotope effects were observed on binding parameters: sites total concentration (N = 1732 microM for 1,3,7-(C2H3)3-caffeine versus 822 microM for caffeine; number of sites (n = 3 for 1,3,7-(C2H3)3-caffeine v. 1 for caffeine); and extent of binding (46% for 1,3,7-(C2H3)3-caffeine v. 27% for caffeine). A study of competition for HSA binding between caffeine and its 1,3,7-(C2H3)3- and 3,7-(C2H3)2-isotopomers confirmed the results obtained in direct binding studies. These isotope effects are discussed in terms of (a) tools for molecular pharmacology, (b) precautions to be taken when such labelled drugs are used in clinical pharmacology.

Caffeine↗
PubMed1987

Determination of binding parameters of macrolides, lincosamides, and streptogramins to Legionella pneumophila.

Parameters of [3H]erythromycin binding to Legionella pneumophila were determined in vitro using both an equilibrium and a kinetic method. Different L. pneumophila serogroups, 1-3, and a virulent strain serogroup, 1, were tested. All strains of bacteria exhibited the same binding pattern, with a dissociation constant of 0.15 microM. Other macrolides, streptogramin B-types, and lincosamides competitively displaced bound erythromycin suggesting that these compounds share common binding sites on the bacteria. Minimum inhibitory concentration (MIC) values for macrolides, streptogramin B-types, and lincosamides were determined with buffered charcoal yeast extract (BCYE) medium. A good correlation (r = 0.994) was found between the corresponding inhibition constants of these antibiotics and their MIC. It was also noted that for lincosamides the microbiological inactivity was associated with a very low bacterium affinity. Thus, it is concluded that binding parameters of these antibiotics reflect their efficacy against L. pneumophila in vitro and may serve as a useful adjunct in developing new compounds.

Anti-Bacterial Agents↗
PubMed1987

Interactions of phenylalkylamines with human lung membrane and microsome preparation.

Lipophilic amines are recognized as important tracers for brain imaging. Their pulmonary accumulation was a drawback for optimal concentration in the brain. We used IMP, HIPDM, IP, amphetamine derivatives to determine the relation between structure and accumulation in the lung. The incubation of phenylalkylamines in competition with 3H-Imipramine, for human lung membrane and microsomes was performed and led to the extraction of a competitive constant (KI). The results showed that the compounds can be classified in order of their decreasing affinity: Iodoamphetamine, iodoisopropylamphetamine, dimethyliodophentermine, hydroxyiodobenzyl propane diamine (HIPDM), isopropylamphetamine and amphetamine. Iodine set in the para position of the ring seemed to increase the affinity of phenylalkylamines for the lung. Adjunction of isopropyl or methyl groups to the lateral chain decreased this affinity.

Amines↗
PubMed1987

Binding of 8-methoxypsoralen to human serum proteins and red blood cells.

Serum binding of 8-methoxypsoralen (8-MOP) was studied by equilibrium dialysis. In therapeutic concentrations, 8-MOP binding in serum was high, 91.4%, and constant, indicating concentration-independent kinetics. This binding involved the two main proteins, human serum albumin and alpha 1-acid glycoprotein, in a saturable process with one class of binding sites (n) and affinity constants (Ka) of 1.295 X 10(4) mol/l and 2.115 X 10(4) mol/l, respectively. Binding to lipoproteins and gamma globulins was negligible and non-saturable in therapeutic concentrations, with nKa values of 0.35, 0.024, 0.013 and 0.0004 mumol/l for VLDL, LDL, HDL and gamma globulins, respectively. Inhibition of 8-MOP serum binding was observed with salicylic acid and indomethacin, but not with diazepam, warfarin or erythromycin. Over a range of therapeutic concentrations, the ration of 8-MOP concentration in red blood cells (RBCs) and in serum was constant at 20.3% and three times higher than would be expected if a simple diffusion of the 8-MOP plasma free fraction (fu) occurred. According to the measured and calculated parameters, simulations of 8-MOP blood binding in pathological states (hypoalbuminaemia with or without inflammation) showed variations of fu which were partially 'buffered' by RBCs. Simulation of 8-MOP protein binding at cutaneous interstitial fluid level showed that fu is approximately 30% and permitted prediction of a decrease of fu available to the epidermis in case of local or systemic inflammation. This may imply an increase in the minimum phototoxic dose relevant for PUVA and explain some cases of 'poor' responsiveness of psoriatic patients to PUVA therapy.

Binding Sites↗