Study of multiple binding constants of dexamethasone with human serum albumin by capillary electrophoresis–frontal analysis and multivariate regression

Zhao, Peng; Zhu, Guijie; Zhang, Weibing; Zhang, Lihua; Liang, Zhen; Zhang, Yukui

doi:10.1007/s00216-008-2373-5

Cited by 17 publications

(22 citation statements)

References 26 publications

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“…59 One may suggest that the observed endocytosis of ZSJ-0228 (Figures 9–11) by tubular epithelial cells is a “bystander” effect associated with the internalization/recycling of albumin by the cells. Due to the potential binding of ZSJ-0228 to albumin, 60,61 it is also possible that the prodrug may piggyback albumin and be internalized through the receptor-mediated endocytic process intended for albumin.…”

Section: Discussionmentioning

confidence: 99%

Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects

et al. 2018

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Nephritis is one of the major complications of systemic lupus erythematosus. While glucocorticoids (GCs) are frequently used as the first-line treatment for lupus nephritis (LN), long-term GC usage is often complicated by severe adverse effects. To address this challenge, we have developed a polyethylene glycol-based macromolecular prodrug (ZSJ-0228) of dexamethasone, which self-assembles into micelles in aqueous media. When compared to the dose equivalent daily dexamethasone 21-phosphate disodium (Dex) treatment, monthly intravenous administration of ZSJ-0228 for two months significantly improved the survival of lupus-prone NZB/W F1 mice and was much more effective in normalizing proteinuria, with clear histological evidence of nephritis resolution. Different from the dose equivalent daily Dex treatment, monthly ZSJ-0228 administration has no impact on the serum anti-double-stranded DNA (anti-dsDNA) antibody level but can significantly reduce renal immune complex deposition. No significant systemic toxicities of GCs (e.g., total IgG reduction, adrenal gland atrophy, and osteopenia) were found to be associated with ZSJ-0228 treatment. In vivo imaging and flow cytometry studies revealed that the fluorescent-labeled ZSJ-0228 primarily distributed to the inflamed kidney after systemic administration, with renal myeloid cells and proximal tubular epithelial cells mainly responsible for its kidney retention. Collectively, these data suggest that the ZSJ-0228’s potent local anti-inflammatory/immunosuppressive effects and improved safety may be attributed to its nephrotropicity and cellular sequestration at the inflamed kidney tissues. Pending further optimization, it may be developed into an effective and safe therapy for improved clinical management of LN.

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Section: Discussionmentioning

confidence: 99%

Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects

et al. 2018

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“…Among above plotting methods, the nonlinear binding isotherm (Eq. (9)), x ‐reciprocal plot and the titration curve plot were reported for multivariate binding interactions 37–47.…”

Section: Binding Fundamentalsmentioning

confidence: 99%

Use of CE for the determination of binding constants

2009

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In the past two decades, CE has been used frequently for the measurement of apparent binding/association constants. CE has numerous advantages, including short analysis times, low sample consumption, simplicity of operation, etc. This review provides a fundamental introduction to binding theory and then summarizes recent applications and advances in the field of CE-based methods for the evaluation of molecular association. The time period for this survey is from 2002 (when our previous review was published) to the present.

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“…According to this study, the conformation of proteins is changed in the presence of drug and the binding occurs via hydrophobic interactions . The HSA‐DXM interaction was also evaluated using CE/FA approach and authors were able to calculate the binding constant using multivariate regression . In all of these studies, the binding between dexamethasone or its ester with proteins was investigated using protein concentrations lower than physiological and to the best of our knowledge there is no study in which physiological conditions were simulated according to both buffer composition and protein concentration.…”

Section: Introductionmentioning

confidence: 99%

Capillary electrophoresis/frontal analysis versus equilibrium dialysis in dexamethasone sodium phosphate‐serum albumin binding studies

Gonciarz¹,

Kuś²,

Szafarz³

et al. 2012

Electrophoresis

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Plasma protein binding of drugs may have significant effect on its pharmacodynamic, toxicological and pharmacokinetic properties, since only the free drug can pass across biological membrane and get to its specific site of action. Many drugs show a high affinity to albumin which is the most abundant plasma protein. In the present study capillary electrophoresis in the frontal analysis mode (CE/FA), as promising technique for assessment of drug-protein interaction was used. The free drug concentration was measured from height of the frontal peak and calculated based on the external drug standard in absence of protein. With a known concentration of total drug, the percentage of protein bound drug was determined. The binding parameters were also estimated based on the equilibrium dialysis experiment which is considered to be a reference method. This study was designed to examine the interaction of dexamethasone sodium phosphate (DXM) with BSA and HSA under simulated physiological conditions (pH 7.4, 67 mM phosphate buffer, I = 0.17). Using fixed, at physiological level, HSA and BSA concentrations and increasing DXM concentrations, the number of binding sites (n) and binding constant (K(a) ) was calculated from both nonlinear regression fitting and Scatchard Plot. Despite some differences, it can be concluded that the CE/FA is comparable with equilibrium dialysis, but since the first one offers advantages such as low sample consumption, short analysis time, and high separation efficiency, it can be used in high-throughput screening of drug protein binding at the early stage of drug discovery. Interspecies differences in binding of a drug to albumins have been observed and it should be taken into account in interpretation of the results.

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Study of multiple binding constants of dexamethasone with human serum albumin by capillary electrophoresis–frontal analysis and multivariate regression

Cited by 17 publications

References 26 publications

Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects

Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects

Use of CE for the determination of binding constants

Capillary electrophoresis/frontal analysis versus equilibrium dialysis in dexamethasone sodium phosphate‐serum albumin binding studies

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