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H Aki

Publications and source records attributed to H Aki.

12 recordsLinked to original sources
PubMed1994

Thermodynamic characterization of drug binding to human serum albumin by isothermal titration microcalorimetry.

Binding sites on human serum albumin (HSA) for anionic drugs and fatty acids have been thermodynamically characterized by microcalorimetry. The binding and the thermodynamic parameters were directly computed from the calorimetric titration data at 37 degrees C in a phosphate buffer (pH 7.4) using one- and two-class binding models. From compensation analyses plotting the molar enthalpy change (delta Hm,i) versus those of the molar free energy (delta Gm,i) and molar entropy (delta Sm,i) for each class of binding sites, HSA binding sites were classified into groups S1, S2, and S3. Group S1 included high-affinity binding sites for site II-bound drugs, such as ibuprofen, flufenamic acid, and ethacrynic acid, and short- or medium-length alkyl-chain fatty acids; group S2 included low-affinity binding sites of site II-bound drugs and long-length alkyl-chain fatty acids; and group S3 contained the high-affinity binding sites for site I-bound drugs, such as phenylbutazone, oxphenbutazone, and warfarin, and long-length alkyl-chain fatty acids. High- and low-affinity bindings sites for salicylic acid and acetylaslicylic acid agreed with the regions of groups S3 and S2, respectively. Groups S1 and S2 were characterized by large negative values of delta Hm,i and delta Sm,i, reflecting van der Waals interaction and hydrogen-bonding formation in low dielectric media, and the main force to stabilize the binding complex in group S3 was a hydrophobic interaction, characterized by a small negative delta Hm,i and minor or positive values of delta Sm,i (entropy-driven).

Anions↗
PubMed1992

Thermodynamic aspects of fatty acids binding to human serum albumin: a microcalorimetric investigation.

Thermodynamic parameters have been evaluated for the binding interaction between human serum albumin (HSA) and unbranched fatty acids (FFA) on the basis of a flow microcalorimetric measurement at pH 7.4 and 37 degrees C by computer-fitting to single- and two-class binding models. The heat of binding increased exothermically with increasing alkyl chain length. FFA with nine or less carbons bound to only one class of binding sites (n = 2) with a binding constant (K) of 10(4) M-1. FFA with ten or more carbons bound to the first class of binding sites with high affinity K in the older of 10(5) to 10(6) M-1, and to the second class with a lower affinity and high capacity. The free energy change of the first class of binding sites (delta G1) became more negative as the chain length of FFA was increased. The enthalpy change per mol of FFA (delta H) decreased at the rate of -7.47 kJ.mol-1.CH-1(2) to a minimum at C9 and then increased due to the hydrophobicity of alkyl chains. Compensation analysis for the i th class of HSA molecule by plotting molar changes of enthalpy (delta Hmi) against entropy (delta Smi) and free energy (delta Gmi) indicates two distinct binding sites. The first class (i = 1) of the long-chain FFA on HSA is an entropy-driven reaction associated with nearly constant values of delta Hm1 (-43.0 +/- 4.8 kJ.mol-1), slightly negative values of delta Sm1 (-47.4 less than or equal to delta Sm1 less than or equal to -8.1 J.mol-1.K-1) and -delta Gm1 values, increasing with increasing alkyl chain length. The second class (i = 2) of the long-chain FFA may lie in the same region as the binding sites of the short- and medium-chain FFA with a linear relationship between delta Hmi-delta Smi.

Algorithms↗
PubMed1991

Drug binding to human erythrocytes in the process of ionic drug-induced hemolysis. Flow microcalorimetric approaches.

Erythrocyte hemolysis induced by cationic phenothiazine derivatives and anionic non-steroidal anti-inflammatory drugs was compared, by flow microcalorimetry, with respect to thermodynamic characteristics for drug binding to intact human erythrocytes. Phenothiazines having high hemolytic activities bound strongly to erythrocyte cells, inducing an immediate hemolytic action characterized by an endothermic heat effect prior to saturating available binding sites. The thermodynamic observable delta H and delta S fell within the ranges of -119 to -65.1 kJ/mol and -308 to -128 J/mol/K, respectively, for these cationic species. There was a linear relationship between the hemolytic activity and the degree of exothermicity of delta H which was enhanced significantly by the presence of a halogen atom(s) at the C-2 position of the phenothiazine nucleus in the order of H less than Cl less than CF3. Anti-inflammatory drugs, however, bound to quite different sites in the erythrocytes with lower affinities and higher capacities than cationic drugs. The latter was characterized by small negative delta H (-17.3 to -7.1 kJ/mol) and positive delta S (10 to 41 J/mol/K). In the calorimetric profiles observed during hemolysis by anionic drugs, two stages were seen: the first, an exothermic process, arising from drug binding to the erythrocytes; the second, an endothermic process, corresponding to the heat of dilution of hemoglobin released from erythrocytes. Hemolysis occurred after the binding sites on the erythrocytes were saturated with drugs. Our data suggest that the binding activities of ionic drugs, such as the amounts of the bound drug and their binding energies to erythrocytes, contribute to the hemolysis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Microcalorimetric study for the binding of ionic drugs to human erythrocytes and the ghost membranes.

The binding of phenothiazine derivatives (as cationic drugs) and non-steroidal anti-inflammatory drugs (as anionic drugs) to human erythrocytes and ghost membranes has been compared with respect to their thermodynamic characteristics, by flow microcalorimetry at pH 7.4 and 37 C. From enthalpyentropy correlation, it was shown that anionic and cationic drugs are bound to different binding sites on the membranes. Phenothiazines bind to a single common site of the erythrocyte membranes with relatively high binding affinities (K = 10(4)-10(5) M-1). The binding is entropy-driven and characterized by a small negative enthalpy (delta H) and a positive entropy change (delta S), reflecting hydrophobic interactions. However, the binding reaction for the intact erythrocytes shows large negative values for both delta H and delta S. The values of K for the membranes and delta H for the intact erythrocytes increased with the increase of the hydrophobic character of the substituent group at the C-2 position of the phenothiazine nucleus (H less than Cl less than CF3). The results indicate that phenothiazines bind and or penetrate to the inner membranes of the erythrocytes and react with intracellular components such as haemoglobin, while anti-inflammatory drugs bind to the surface protein on the membranes with a lower affinity (K = 10(3) M-1) than phenothiazines, reflecting the small negative delta H and positive delta S for the interaction with intact erythrocytes.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Inhibitory effect of beta-cyclodextrin on ampicillin polymerization in aqueous solution.

Ampicillin polymerizes in aqueous solution to produce antigenic polymers; the polymers were separated by anion-exchange chromatography and shown to consist of a dimer, trimer, tetramer and pentamer of ampicillin by the masses found in fast atom bombardment mass spectroscopy. The presence of an intact beta-lactam ring in each of the polymers was revealed by the characteristic positive Cotton effect near 230 nm in their circular dichroism spectra. beta-Cyclodextrin was found to inhibit this polymerization by complex formation involving equimolar quantities of the constituents. Formation of this complex was complete in 10% aqueous solution within 6 hr at 24 degrees C. The positive Cotton effect arising from the beta-lactam ring decreased as the degree of polymerization increased, but was unchanged by the complex formation with beta-cyclodextrin.

Ampicillin↗
PubMed1989

Thermodynamics of the binding of phenothiazines to human plasma, human serum albumin and alpha 1-acid glycoprotein: a calorimetric study.

A flow microcalorimetric study has been carried out to investigate the interactions between phenothiazine derivatives and human plasma, human serum albumin (HSA) and alpha 1-acid glycoprotein (AGP) at pH 7.4 and 37 degrees C. The direct analyses of enthalpic titration curves allowed the determination of the binding enthalpy change (delta H), the apparent binding constant (K), and the number of the binding sites (n), as well as the evaluation of the apparent free energy (delta G), and entropy (delta S) changes. The overall binding of phenothiazines was exothermic with negative delta H, which was compensated for by changes in delta S. The values of delta G were relatively insensitive to variation in the molecular details of the binding reaction. HSA possessed two classes of binding sites for phenothiazines. The first (n1 = 1), with high affinity (K1 = 10(5)-10(6) M-1) was characterized by small negative delta H and positive delta S values due to hydrophobic interaction. The second class of sites had a low affinity (K2 = 10(3)-10(4) M-1) and high capacity (n2 = 3-8) and contributed to the negative delta H and delta S values. The binding and thermodynamic parameters were influenced by the aliphatic side chain moieties on the phenothiazine nucleus. On the other hand, the drugs were bound to AGP at a single common binding site with a binding affinity of the order of 10(4)M-1, characterized by negative delta H and delta S values, which partially reflected the effect of a van der Waals' interaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1988

Application of differential flow microcalorimetry for study of drug interactions in the blood system.

A compact differential flow microcalorimeter has been developed to investigate biomolecular reactions, especially drug interactions in the blood system. The calorimeter is an adiabatic type and consists of a twin-cell structure, each mixing part having a volume of 60 microliters. Both the precision and accuracy of the instrument have been evaluated by dilution of sucrose solutions to be 0.1-0.5% at a heat effect of 100-10 microW. The resolution is approximately 0.5 microW (less than 10(-3) Torr). The heat produced in erythrocyte hemolysis induced by chlorpromazine hydrochloride (CPZ) and the binding heat of CPZ to human blood components viz., intact erythrocytes, erythrocyte membranes, serum albumin and plasma were measured. The heat effect of hemolysis was endothermic and related to the quantity of free hemoglobin released from erythrocytes. The overall binding of CPZ to blood components was, however, an exothermic process. The thermodynamic and binding parameters were computed directly from the calorimetric data by use of a nonlinear least squares regression method, assuming a one-class binding model, and the stoichiometry of the binding reaction was determined.

Blood Proteins↗