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首页> 外文期刊>Journal of pharmaceutical sciences. >Accumulation of BNP7787 in human renal proximal tubule cells.
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Accumulation of BNP7787 in human renal proximal tubule cells.

机译：BNP7787在人肾近端小管细胞中的积累。

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摘要

BNP7787, an investigational drug undergoing global Phase III development, appears to have potential advantages over other cytoprotective compounds that have been evaluated for preventing and mitigating cisplatin-induced nephrotoxicity. Herein, we characterized the in vitro accumulation of BNP7787 in human renal proximal tubule cells (HK-2) in which cisplatin is known to be taken up and accumulate. HK-2 cells were incubated with pharmacological concentrations of BNP7787 for varying times. Temperature-dependent accumulation of BNP7787 in cells was observed and the BNP7787-derived metabolite, mesna, formed intracellularly was directly monitored. The peak level of BNP7787-derived mesna measured in HK-2 cells was approximately 0.6 nmol/10(6) cells; this is pharmacologically similar to reported platinum concentrations in kidney cells and may be sufficient to afford nephroprotection. Therefore, in addition to previously suggested glomerular filtration, the cellular accumulation of BNP7787 by HK-2 cells is a plausible newly identified mechanism by which BNP7787 may accumulate in renal tubular cells, where it can exert its pharmacological effects to protect against cisplatin-induced nephrotoxicity by direct covalent conjugation of mesna with cisplatin, or by the formation of BNP7787-derived mesna-disulfide heteroconjugates that exert nephroprotective effects by inhibition of the key toxification enzyme targets gamma-glutamyltranspeptidase and aminopeptidase N.
机译：BNP7787，一种正在进行全球III期开发的研究药物，似乎比其他已被评估用于预防和减轻顺铂诱导的肾毒性的细胞保护化合物具有潜在的优势。本文中，我们表征了BNP7787在人肾近端小管细胞（HK-2）中的体外蓄积，其中已知顺铂被吸收并蓄积。 HK-2细胞与药理浓度的BNP7787孵育不同的时间。观察到BNP7787在细胞中的温度依赖性积累，并直接监测BNP7787衍生的代谢产物mesna在细胞内形成。在HK-2细胞中测得的BNP7787衍生的mesna的峰值水平约为0.6 nmol / 10（6）细胞;这在药理上类似于所报道的肾细胞中铂的浓度，可能足以提供肾保护作用。因此，除先前建议的肾小球滤过外，HK-2细胞对BNP7787的细胞蓄积是一种可能被新发现的机制，通过该机制，BNP7787可能在肾小管细胞中蓄积，在该机制中它可以发挥药理作用来防止顺铂诱导的肾毒性。通过直接与顺铂共价修饰mesna，或形成BNP7787衍生的mesna-二硫键杂合物，通过抑制关键的毒化酶靶向γ-谷氨酰转肽酶和氨肽酶N发挥肾保护作用。

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