Verschraagen M, Boven E, Torun E, Erkelens C A M, Hausheer F H, van der Vijgh W J F
Department of Medical Oncology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1007 MB Amsterdam, The Netherlands.
Br J Cancer. 2004 Apr 19;90(8):1654-9. doi: 10.1038/sj.bjc.6601719.
In preclinical studies, BNP7787 (disodium 2,2'-dithio-bis-ethane sulphonate), the disulphide form of mesna, has demonstrated selective protection against cisplatin-induced nephrotoxicity due to conversion into mesna inactivating toxic platinum species. Mesna (sodium 2-mercapto ethane sulphonate), however, can affect the antitumour activity of cisplatin, while BNP7787 does not interfere with the antitumour activity. To understand the difference in interference with cisplatin-induced antitumour activity between BNP7787 and mesna as well to characterise the selective nephroprotection by BNP7787, the pharmacokinetics of BNP7787 and mesna, each given i.v. 1000 mg x kg(-1), were determined in plasma, kidney, liver, red blood cells (RBC), skeletal muscle and tumour of Fischer rats bearing subcutaneously implanted WARD colon tumours. The following results were obtained: (1). high concentrations of BNP7787 and mesna were observed in the plasma and kidney after administration of BNP7787 or mesna, except for mesna in plasma after BNP7787 administration; (2). in all other sampled compartments, the AUC values of both compounds were at least 5.5-fold lower than the corresponding values in kidney; (3). the AUC of mesna in plasma after mesna administration was comparable to the AUC of mesna in kidney after a dose of BNP7787 that can completely prevent cisplatin-induced nephrotoxicity in rats; (4). the AUC of mesna in plasma was five-fold higher relative to the AUC of mesna following BNP7787 administration (P<0.01). In conclusion, the five-fold higher AUC of mesna in plasma after mesna administration and the fact that mesna is more reactive with (hydrated) cisplatin than its disulphide form BNP7787 represent a plausible explanation as to why mesna administration can reduce the antitumour activity of cisplatin. After BNP7787 administration, the distribution of BNP7787 and mesna was restricted to the kidney, which confirmed the selective protection of the kidney by BNP7787.
在临床前研究中，BNP7787（2,2'-二硫代双乙烷磺酸钠），即美司钠的二硫化物形式，已证明可通过转化为美司钠使有毒铂类物质失活，从而对顺铂诱导的肾毒性具有选择性保护作用。然而，美司钠（2-巯基乙烷磺酸钠）会影响顺铂的抗肿瘤活性，而BNP7787不会干扰其抗肿瘤活性。为了解BNP7787和美司钠在干扰顺铂诱导的抗肿瘤活性方面的差异，并表征BNP7787的选择性肾保护作用，对皮下植入WARD结肠肿瘤的Fischer大鼠静脉注射1000 mg·kg⁻¹的BNP7787和美司钠后，分别在血浆、肾脏、肝脏、红细胞（RBC）、骨骼肌和肿瘤中测定了它们的药代动力学。得到以下结果：（1）. 给予BNP7787或美司钠后，血浆和肾脏中观察到高浓度的BNP7787和美司钠，但BNP7787给药后血浆中的美司钠除外；（2）. 在所有其他采样隔室中，两种化合物的AUC值均至少比肾脏中的相应值低5.5倍；（3）. 美司钠给药后血浆中美司钠的AUC与能完全预防大鼠顺铂诱导的肾毒性的BNP7787剂量给药后肾脏中美司钠的AUC相当；（4）. 美司钠给药后血浆中美司钠的AUC相对于BNP7787给药后美司钠的AUC高五倍（P<0.01）。总之，美司钠给药后血浆中美司钠的AUC高五倍，以及美司钠比其二硫化物形式的BNP7787与（水合）顺铂反应性更强这一事实，为美司钠给药为何会降低顺铂的抗肿瘤活性提供了一个合理的解释。给予BNP7787后，BNP7787和美司钠的分布局限于肾脏，这证实了BNP7787对肾脏的选择性保护作用。
