Enantioselective binding of disopyramide to α 1 -acid glycoprotein and its variants

The mean plasma AAG concentration in the female subjects was significantly lower than that in the male subjects (0.67 +/- 0.12 mg/ml, mean +/- SD, in females, n = 15, versus 0.81 +/- 0.17 mg/ml in males, n = 17, P < 0.05), but no age-related differences were found (0.75 +/- 0.18 mg/ml in young subjects, n = 24, versus 0.77 +/- 0.12 mg/ml in older subjects, n = 8, n.s.). However, the degree of branching of the glycan chain in the female subjects was significantly lower than that in the male subjects (1.61 +/- 0.17 mol/mol, mean +/- SD, in females, n = 15, versus 1.75 +/- 0.23 mol/mol in males, n = 17, P < 0.05). There was a significant inverse relationship between the binding capacity of AAG to DP (Cb/AAG) and the degree of branching of the glycan chain. The binding capacity (Cb/AAG) decreased as the degree of branching in AAG glycans increased. The binding capacity (Cb/AAG) in the female subjects was significantly higher than that in the male subjects (2.79 +/- 0.59 mg/g AAG in females, mean +/- SD, n = 15, versus 2.37 +/- 0.29 mg/g AAG in males, n = 17, P < 0.05). CONCLUSION. The degree of branching of the glycan chain in AAG plays an important role in drug-binding capacity. Gender-related differences in drug-binding capacity (Cb/AAG) may be caused by differences in the ratios of the extent of branching of the glycan chain in AAG.

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Age- and gender-related differences in carbohydrate concentrations of α 1 -acid glycoprotein variants and the effects of glycoforms on their drug-binding capacities

Kishino

Nomura

Itoh

et al. 2002

European Journal of Clinical Pharmacology

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Chiral Interactions of the Drug Propranolol and α₁-Acid-Glycoprotein at a Micro Liquid–Liquid Interface

Lopes

Kataky

2012

Anal. Chem.

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The investigation of chiral interactions of drugs with plasma proteins is of fundamental importance for drug efficacy and toxicity studies. In this paper, we demonstrate a simple liquid-liquid interface procedure for investigating chiral interactions. Chiral discrimination of the enantiomers of a basic drug, propranolol, was achieved at a micro liquid-liquid interface, using α(1)-acid-glycoprotein (AGP) as a chiral acute phase plasma protein. When the protein is added to an aqueous phase containing the enantiomers of propranalol hydrochloride, the binding of (S)- and (R)-propranolol hydrochloride to the protein results in a decrease in the cyclic voltammetry (CV) and differential pulse voltammetry (DPV) current responses corresponding to the decrease in transfer of propranolol at an aqueous-1,2-dichloroethane interface. This decrease is a consequence of the complexation of the drug and the protein. The complex drug-protein does not transfer across the interface nor changes the transfer potential of the uncomplexed form of propranolol enantiomers. The bound concentration of propranolol enantiomers in the presence of AGP was found to be greater for (S)-propranolol than (R)-propranolol for solutions containing constant concentrations of AGP (50 μM). Scatchard analysis yielded association constants of 2.7 and 1.3 × 10(5) M(-1) for (S)- and (R)-propranolol, respectively.

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Differential binding of disopyramide and warfarin enantiomers to human α₁‐acid glycoprotein variants

Nakagawa

Kishino

Itoh

et al. 2003

Brit J Clinical Pharma

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Aims The F1S and A genetic variants of a 1 -acid glycoprotein (AAG) change under various physiological and pathological conditions. They also vary in their drug binding abilities. We have studied the stereoselective binding ability of each of the AAG variants using enantiomers of disopyramide (DP) and warfarin (WR). Methods The AAG variants were separated by hydroxyapatite chromatography. Binding of drug enantiomers to the AAG variants was studied by the HummelDreyer method. The characteristics of the binding activities were examined by Scatchard plot analysis. The first five amino-terminal amino acids (residues 112-116) of the cyanogen bromide (CNBr) fragment (residues 112-181) of each of the separated AAG fractions were elucidated by Edman degradation. Results Commercial AAG was separated into two main fractions. Residues 112-116 of fraction 2 were identical to the amino acid sequences predicted from the AAG A gene, LAFDV, and encode the F1S variant. In fraction 3, the deduced amino acid sequence of the AAG B gene, FGSYL, was established, and encodes the A variant. The binding affinities of both DP enantiomers in fraction 3 were significantly higher than those in fraction 2. The differences between dissociation constants (Kd) in fractions 2 and 3 were 5.2-fold for (S)-DP ( P < 0.05) and 3.7-fold for (R)-DP ( P < 0.001). The dissociation constant of (S)-DP (0.39 ± 0.08 m M ) was lower than that of (R)-DP (0.53 ± 0.10 m M ) in fraction 3 [95% confidence interval (CI) -0.282, -0.010; P < 0.05], although the binding activities of the DP enantiomers were almost the same in fraction 2. By contrast WR enantiomers had a higher binding affinity in fraction 2 than in fraction 3, the differences in dissociation constants between fractions 2 and 3 being 12.6-fold for (S)-WR ( P < 0.001) and 8.3-fold for (R)-WR ( P < 0.001). The dissociation constant of (S)-WR (0.28 ± 0.10 m M ) was significantly lower than that of (R)-WR (0.48 ± 0.08 m M ) in fraction 2 (95% CI -0.369, -0.028; P < 0.05), but there were no significant differences between the binding activities of WR enantiomers in fraction 3. Conclusions DP and WR enantiomers bind preferentially to fraction 3 and fraction 2, respectively. Fractions 2 and 3 are encoded by the AAG A and the AAG B genes, respectively.

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Enantioselective binding of disopyramide to α 1 -acid glycoprotein and its variants

Abstract: The difference between the binding capacities of S-DP and R-DP is due to differences in the association of DP to variants 3-6, and the role of the variants 1 and 2 in the binding of drugs to AAG is minor.

Cited by 5 publications

References 20 publications

Age- and gender-related differences in carbohydrate concentrations of α 1 -acid glycoprotein variants and the effects of glycoforms on their drug-binding capacities

Age- and gender-related differences in carbohydrate concentrations of α 1 -acid glycoprotein variants and the effects of glycoforms on their drug-binding capacities

Chiral Interactions of the Drug Propranolol and α₁-Acid-Glycoprotein at a Micro Liquid–Liquid Interface

Differential binding of disopyramide and warfarin enantiomers to human α₁‐acid glycoprotein variants

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Enantioselective binding of disopyramide to α 1 -acid glycoprotein and its variants

Abstract: The difference between the binding capacities of S-DP and R-DP is due to differences in the association of DP to variants 3-6, and the role of the variants 1 and 2 in the binding of drugs to AAG is minor.

Cited by 5 publications

References 20 publications

Age- and gender-related differences in carbohydrate concentrations of α 1 -acid glycoprotein variants and the effects of glycoforms on their drug-binding capacities

Age- and gender-related differences in carbohydrate concentrations of α 1 -acid glycoprotein variants and the effects of glycoforms on their drug-binding capacities

Chiral Interactions of the Drug Propranolol and α1-Acid-Glycoprotein at a Micro Liquid–Liquid Interface

Differential binding of disopyramide and warfarin enantiomers to human α1‐acid glycoprotein variants

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Product

Resources

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Chiral Interactions of the Drug Propranolol and α₁-Acid-Glycoprotein at a Micro Liquid–Liquid Interface

Differential binding of disopyramide and warfarin enantiomers to human α₁‐acid glycoprotein variants