Characterizing the interactions of the antipsychotic drug trifluoperazine with bovine serum albumin: Probing the drug-protein and drug-drug interactions using multi-spectroscopic approaches (original) (raw)
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Radioimmunoassay for trifluoperazine in human plasma
British Journal of Clinical Pharmacology, 1981
1 A new sensitive and rapid radioimmunoassay procedure for the determination of the plasma concentrations of the neuroleptic drug trifluoperazine is described. 2 The antiserum developed for trifluoperazine cross‐reacted with N‐desmethyltrifluoperazine and 7‐ hydroxytrifluoperazine to the extent of 26 and 24% respectively but its cross‐reactivity with commonly co‐administered tricyclic antidepressants and antianxiety agents tested was negligible. 3 The assay, based on the above antiserum, enabled the quantitation of 50 pg of the drug in 200 microliters of plasma with a coefficient of variation of about 2% and therefore should be applicable for singly dose pharmacokinetic and bioavailability studies. It should be applicable to therapeutic monitoring of the drug in patients.
Journal of Electrochemical Science and Engineering, 2016
The interaction between perazine dimaleate (PDM) and bovine serum albumin (BSA) was investigated by voltammetry, fluorescence spectroscopy, UV-vis spectroscopy, molecular docking and viscometric methods. The study was carried out in acetate buffer solution of pH 7.2, which was prepared by using 0.1 M sodium acetate and adjusting pH using 0.1 M hydrochloric acid. The voltammetric study of PDM shows a pair of well redox peaks at 0.538 and 0.471 V (versus SCE) on a GCE in acetate buffer of pH 7.2 at 50 mV s-1. After the addition of BSA into the PDM solution, the redox peak currents decreased gradually, and peak potentials shifted towards negative direction. The results of voltammetry, fluorescence quenching and UV-vis absorption spectra experiments indicated the formation BSA-PDM complex. The binding parameters like binding constant and binding free energy were determined from voltammetric data. The binding constant and binding energy was also determined from UV-vis and fluorescence spectroscopy with a value quite close to that obtained from CV.
Effect of Glycation of Hemoglobin on its Interaction with Trifluoperazine
The Protein Journal, 2006
Trifluoperazine (TFZ), a phenothiazine drug, penetrates into human erythrocytes and releases oxygen by interaction with hemoglobin. TFZ-induced oxygen release from hyperglycemic erythrocytes isolated from diabetic patients is considerably less compared to that from the cells of normoglycemic individuals. In diabetes mellitus, hemoglobin is significantly glycated by glucose. Non-glycated hemoglobin, HbA 0 and its major glycated analog, HbA 1c have been separated from the blood samples of diabetic patients. TFZ releases considerable amount of oxygen from HbA 0 , but very little from HbA 1c . Spectrofluorimetric studies reveal that TFZ forms excited state complexes with both HbA 0 and HbA 1c . Titration of HbA 0 with TFZ in a spectrophotometric study exhibits two isosbestic points. Similar experiment with HbA 1c causes gradual loss of the Soret peak without appearance of any isosbestic point indicating a possibility of heme loss during interaction, which is also supported by gel filtration experiment and SDS-PAGE experiment followed by heme staining. The results suggest that drug action on hemoglobin is influenced by glycation-induced structural modification of the protein.
Thermodynamics study of binding of oxazepam and flurazepam to Human Serum
Iranian Journal of Basic Medical Sciences, 2005
Objective: HSA is the highly water-soluble plasma protein, which is the smallest and most abundant plasma protein in the human body. Oxazepam (O) and Flurazepam (F) include the most frequently prescribed sedative-hypnotic agents. (F) and (O) bind to human serum proteins more than 95%. Investigations show that HSA has an important role as a carrier for diazepins. The interaction of drugs with HSA, which may have important pharmacokinetics implications, has been extensively studied by several workers. Materials and Methods: The binding of two diazepins [Oxazepam (O) and Flurazepam (F)] to HSA was investigated by means of spectrophotometry. The binding isotherms for interaction of (F) and (O) with HSA at 25 ˚C shows the variation of ν, the average of bound (O) and (F) per HSA molecule, versus log [D]. The corresponding Scatchard plots for these isotherms were driven. They coincide with usual shapes of Scatchard plots and can represent the existence of one binded set. The binding parameters, binding constant and binding capacity of these medicines were obtained from Hill equation. Results: The binding constants of Flurazepam (F) and Oxazepam (O) were determined 0.6 ± 0.1(x10 5) and 1.4 ± 0.3 (x10 5) respectively. The binding capacity of (F) and (O) were computed 1 ± 0.1 and 1.3 ± 0.1, and the Hill constant (n H) was obtained 4.076 and 2.44 respectively. The results of this study show, spectrophotometry can be a simple and fast technique to determine the binding constant for some ligands. Conclusion: These values show the binding affinity of (O) is more than (F), on the other hand, the cooperativity of (F); is higher than (O). With regards to the amount of K, binding affinity of (O) to HSA is more than (F). These results can be justified by the amounts of partition coefficient of (O) and (F).
Membrane effects of trifluoperazine, dibucaine and praziquantel on human erythrocytes
Chemico-Biological Interactions, 2000
Trifluoperazine (TFP) is a potent antipsychotic agent, dibucaine (DBC) is a local anaesthetic and praziquantel (PZQ) is a highly effective agent against schistosomiasis. The present work was conducted to (i) investigate the cytotoxic effects of TFP, DBC and PZQ on human erythrocyte membranes; and (ii) compare the alterations induced by the cationic drugs (TFP and DBC) with those induced by the uncharged compound (PZQ), in an attempt to have a better insight on the pathways of each drug-membrane interaction. The erythrocyte morphological alterations induced by sublytic concentrations of TFP, DBC and PZQ were evaluated by scanning electron microscopy and expressed quantitatively by the morphological index. Haemolysis and release of membrane lipids (phospholipids and cholesterol) produced by selected concentrations of TFP, DBC and PZQ, were compared with those resulting from the corresponding triple concentrations of each drug. Our results showed that the uncharged molecule of PZQ induces the same morphological alterations (stomatocytosis) as the cationic drugs TFP and DBC. Haemolysis was shown to vary with the drug used and to be concentration-dependent, with values 10-fold more elevated for TFP and DBC than for PZQ, which revealed a maximum of 6% haemolysis for the highest concentration tested. Different concentration-response curves were obtained for lipid elution, although the profiles of cholesterol and phospholipids released were similar for all drugs. Nevertheless, at a fixed rate of 50% haemolysis, TFP induced a 2-fold increment in the elution of cholesterol when compared with that produced by DBC
Contribution of trifluoperazine/lipid ratio and drug ionization to hemolysis
Biochimica et Biophysica Acta (BBA) - Biomembranes, 1998
The interaction of the antipsychotic drug trifluoperazine (TFP) with membranes was investigated in terms of lipid phase perturbation. TFP partition coefficients (P) were measured by phase separation between octanol/water and model membranes/water. The profile of P values at pH 7.4 was: microsomes (7172+ 1229) > liposomes (1916+ 341) > erythrocyte ghosts (1380_+429)> octanol (452_+55). Hemolytic experiments showed a biphasic, protective (at lower concentrations) and hemolytic effect above the CMC (42 ~tM at pH 7.4) of the phenothiazine. By applying classical treatments for surface active compounds to the hemolytic curves, we could calculate P values in whole erythrocyte cells. The preferential binding of uncharged to charged TFP in the membrane was discussed, since it results in a ionization constant (pKapp) different from that observed in the aqueous phase (pK). The TFP ionization constant was decreased from 8.1 (in water) to 7.62 in the presence of membranes and almost the same ratio of charged/uncharged TFP species is present at physiologic pH. Taking into account the ApK, we calculated the average TFP partition coefficient between egg phosphatidylcholine liposomes and water, at pH 7.4 (P ..... ge = 1432), which was well correlated with the measured one (plip= 1916). Paverage is highly influenced by the uncharged TFP species and the real base/acid ratio under physiologic conditions was discussed in terms of its possible role in the biological activity of TFP.
Binding of trifluoperazine and fluorene-containing compounds to calmodulin and adducts
Biochemical Pharmacology, 1986
Calmodulin can be specifically acylated with a fluorene-containing hydrophobic spin-labeling reagent at just Lys 75 or at Lys 75 and Lys 148. The binding of trifluoperazine to calmodulin and the two adducts was determined using a Hummel-Dreyer procedure, and binding of the phenothiazine was found to be characterized by apparent positive cooperativity and an apparent limiting stoichiometrv of about seven binding sites per protein molecule. Two non-reactive fluorene-containing compounds were synthesized, and both reagents exhibited far less binding to calmodulin than did trifluoperazine. One of these was also assayed for binding to the monolabeled adduct, and this binding was about half that observed with calmodulin and was non-cooperative. Thus, the qualitative and quantitative binding parameters of hydrophobic groups to calmodulin can be quite different.
Estimation of plasma protein binding of selected antipsychotics using computed molecular properties
Archives of Biological Sciences
The plasma protein binding (PPB) data of twelve antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, chlorpromazine, flupentixol, fluphenazine, haloperidol, zuclopenthixol) were estimated using computed molecular descriptors, which included the electronic descriptor-polar surface area (PSA), the constitutional parameter-molecular weight (Mw), the geometric descriptor-volume value (Vol), the lipophilicity descriptor (logP) and aqueous solubility data (logS), and the acidity descriptor (pK a). The relationships between computed molecular properties of the selected antipsychotics and their PPB data were investigated by simple linear regression analysis. Low correlations were obtained between the PPB data of the antipsychotics and PSA, Mw, Vol, pKa, logS (R <0.30) values, while relatively higher correlations (0.35<R 2 <0.70) were obtained for the majority of logP values. Multiple linear regression (MLR) analysis was applied to access reliable correlations of the PPB data of the antipsychotics and the computed molecular descriptors. Relationships with acceptable probability values (P<0.05) were established for five lipophilicity descriptors (logP values) with application of the acidity descriptor (pKa) as independent variables: AlogP (R 2 =0.705), XlogP3 (R 2 =0.679), ClogP (R 2 =0.590), XlogP2 (R 2 =0.567), as well as for the experimental lipophilicity parameter, logPexp (R 2 =0.635). The best correlations obtained in MLR using AlogP and pKa as independent variables were checked using three additional antipsychotics: loxapine, sulpiride and amisulpride, with the PPB values of 97%, "less than" 40% and 17%, respectively. Their predicted PPB values were relatively close to the literature data. The proposed technique confirmed that lipophilicity, together with acidity significantly influences the PPB of antipsychotics. The described procedure can be regarded as an additional in vitro approach to the modeling of the investigated group of drugs.