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Analysis of BNP7787 thiol-disulfide exchange reactions in phosphate buffer and human plasma using microscale
Dakshine Shanmugarajah1, Daoyuan Ding, Quili Huang
1BioNumerik Pharmaceuticals, Inc. 8122 Datapoint Drive, Suite 400, San Antonio, TX 78229, USA.
Abstract:
BNP7787 (disodium 2,2'-dithio-bis ethane sulfonate; Tavocept) is a novel water-soluble investigational agent that is undergoing clinical development for prevention and mitigation of cisplatin-induced nephrotoxicity. BNP7787 is a disulfide that undergoes thiol-disulfide exchange reactions in vivo with physiological thiols. Mesna-disulfide heteroconjugates that form as a result of these exchange reactions may play a key role in the protection against cisplatin-induced nephrotoxicity. Although several analytical methods have been used to detect thiols and disulfides, they have notable limitations including (i) low sensitivity, (ii) interference by chemical modification by derivatization reagents, and (iii) cumbersome sample preparation. In this paper, a sensitive micro-HPLC-EC method is described that identifies BNP7787 and mesna in plasma and phosphate buffer across a broad concentration range from 500nM to 100microM. This method utilizes a dual electrochemical detector equipped with a wall-jet gold electrode. The approach described here facilitates the identification of BNP7787 and mesna down to nanomolar levels. Although we did not focus on optimizing the approach for other thiol and disulfide compounds, we believe this approach could be optimized and used in the identification of other thiols and disulfides in plasma. The assay requires significantly less sample preparation and does not involve the use of derivatizing agents (i.e., the thiol and disulfide species can be detected directly) and represents an important advance over previous methods. This method was used to detect and quantitate BNP7787 and to monitor and kinetically characterize the interactions of BNP7787 with glutathione, cysteine, cysteinyl-glycine, cysteinyl-glutamate and homocysteine.
Insights
A new analytical method accurately detects BNP7787 (Tavocept) and mesna in plasma. This sensitive technique aids in understanding cisplatin-induced nephrotoxicity and developing protective agents.
Area of Science:
- Analytical Chemistry
- Pharmacology
- Toxicology
Background:
- Cisplatin chemotherapy can cause severe kidney damage (nephrotoxicity).
- BNP7787 (Tavocept) is an investigational agent designed to prevent and mitigate cisplatin-induced nephrotoxicity.
- Existing analytical methods for thiols and disulfides have limitations in sensitivity, sample preparation, and potential for chemical interference.
Purpose of the Study:
- To develop and validate a sensitive analytical method for detecting BNP7787 and its metabolite mesna in biological samples.
- To overcome the limitations of existing analytical techniques for thiol and disulfide quantification.
- To facilitate the study of BNP7787's mechanism of action in preventing cisplatin-induced nephrotoxicity.
Main Methods:
- Development of a micro-High-Performance Liquid Chromatography coupled with Electrochemical Detection (micro-HPLC-EC) method.
- Utilization of a dual electrochemical detector with a wall-jet gold electrode for direct detection of thiols and disulfides.
- Analysis of BNP7787 and mesna in plasma and phosphate buffer across a concentration range of 500 nM to 100 µM.
Main Results:
- The developed micro-HPLC-EC method demonstrated high sensitivity, detecting BNP7787 and mesna at nanomolar levels.
- The assay requires minimal sample preparation and avoids derivatization agents, allowing direct detection of thiol and disulfide species.
- The method was successfully applied to quantitate BNP7787 and characterize its in vitro interactions with physiological thiols like glutathione and cysteine.
Conclusions:
- A novel, sensitive, and direct micro-HPLC-EC method has been established for the analysis of BNP7787 and mesna.
- This method offers significant advantages over previous analytical techniques, improving efficiency and reducing potential interferences.
- The validated method is crucial for pharmacokinetic studies, therapeutic monitoring, and further research into the protective mechanisms of BNP7787 against cisplatin-induced nephrotoxicity.
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