Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Cancer Chemother Pharmacol. 2013 Dec;72(6):1195-204. doi: 10.1007/s00280-013-2296-5. Epub 2013 Sep 24.
Benzaldehyde dimethane sulfonate (DMS612, NSC281612, BEN) is an alkylator with activity against renal cell carcinoma, currently in phase I trials. In blood, BEN is rapidly metabolized into its highly reactive carboxylic acid (BA), presumably the predominant alkylating species. We hypothesized that BEN is metabolized to BA by aldehyde dehydrogenase (ALDH) and aimed to increase BEN exposure in blood and tissues by inhibiting ALDH with disulfiram, thereby shifting BA production from blood to tissues.
Female CD2F1 mice were dosed with 20 mg/kg BEN iv alone or 24 h after 300 mg/kg disulfiram ip. BEN, BA, and metabolites were quantitated in plasma and urine, and toxicities were assessed.
BEN had a plasma t½ <5 min and produced at least 12 products. The metabolite half-lives were <136 min. Disulfiram increased BEN plasma exposure 368-fold (AUC0-inf from 0.11 to 40.5 mg/L min), while plasma levels of BA remained similar. Urinary BEN excretion increased (1.0-1.5 % of dose), while BA excretion was unchanged. Hematocrit, white blood cell counts, and percentage lymphocytes decreased after BEN administration. Coadministration of disulfiram appeared to enhance these effects. Profound liver pathology was observed in mice treated with disulfiram and BEN.
BEN plasma concentrations increased after administration of disulfiram, suggesting that ALDH mediates the rapid metabolism of BEN in vivo, which may explain the increased toxicity seen with BEN after administration of disulfiram. Our results suggest that the coadministration of BEN with drugs that inhibit ALDH to patients that are ALDH deficient may cause liver damage.
苯甲醛二甲磺酸酯（DMS612，NSC281612，BEN）是一种烷化剂，对肾细胞癌具有活性，目前正在进行 I 期临床试验。在血液中，BEN 迅速代谢为其高反应性羧酸（BA），推测 BA 是主要的烷化剂。我们假设 BEN 通过醛脱氢酶（ALDH）代谢为 BA，并通过抑制 ALDH 用双硫仑增加血液和组织中的 BEN 暴露，从而将 BA 的产生从血液转移到组织中。
雌性 CD2F1 小鼠单独静脉注射 20 mg/kg BEN 或静脉注射 300 mg/kg 双硫仑 24 小时后静脉注射 20 mg/kg BEN。在血浆和尿液中定量测定 BEN、BA 和代谢物，并评估毒性。
BEN 的血浆半衰期<5 分钟，产生至少 12 种产物。代谢物半衰期<136 分钟。双硫仑使 BEN 的血浆暴露量增加 368 倍（AUC0-inf 从 0.11 至 40.5 mg/L min），而 BA 的血浆水平保持不变。BEN 的尿排泄增加（剂量的 1.0-1.5%），而 BA 的尿排泄不变。红细胞压积、白细胞计数和淋巴细胞百分比在 BEN 给药后下降。双硫仑的给药似乎增强了这些作用。用双硫仑和 BEN 治疗的小鼠观察到严重的肝病理。
双硫仑给药后 BEN 的血浆浓度增加，提示 ALDH 介导 BEN 在体内的快速代谢，这可能解释了双硫仑给药后 BEN 毒性增加的原因。我们的结果表明，BEN 与抑制 ALDH 的药物联合使用可能会导致 ALDH 缺乏的患者肝脏损伤。
