Effects of the aldehyde dehydrogenase inhibitor disulfiram on the plasma pharmacokinetics, metabolism, and toxicity of benzaldehyde dimethane sulfonate (NSC281612, DMS612, BEN) in mice.
Effects of the aldehyde dehydrogenase inhibitor disulfiram on the plasma pharmacokinetics, metabolism, and toxicity of benzaldehyde dimethane sulfonate (NSC281612, DMS612, BEN) in mice.
复制标题
DOI：
10.1007/s00280-013-2296-5
复制
发表时间：
2013-12
影响因子：
3
通讯作者：
Eiseman, Julie L.
中科院分区：
文献类型：
--
作者：
Parise, Robert A.;Beumer, Jan H.;Clausen, Dana M.;Rigatti, Lora H.;Ziegler, Judy A.;Gasparetto, Maura;Smith, Clayton A.;Eiseman, Julie L.
苯甲醛二甲烷磺酸盐（DMS612, NSC281612， BEN）是一种具有抗肾细胞癌活性的烷基化剂，目前处于I期临床试验。在血液中，BEN被迅速代谢成高活性的羧酸（BA），可能是主要的烷基化物质。我们假设BEN通过醛脱氢酶（ALDH）代谢为BA，目的是通过用双硫仑抑制ALDH，从而将BA的产生从血液转移到组织，从而增加BEN在血液和组织中的暴露。雌性CD2F1小鼠单独给药BEN iv 20 mg/kg或给药双硫仑300 mg/kg后给药24 h。测定血浆和尿液中的BEN、BA和代谢物，并评估毒性。BEN的血浆时间小于5分钟，产生至少12个产物。代谢物半衰期<136 min。双硫仑使BEN血浆暴露量增加368倍（auc0 - info从0.11 mg/L•min增加到40.5 mg/L•min），而血浆BA水平保持不变。尿BEN排泄增加（剂量的1.0% ~ 1.5%），BA排泄不变。给药后，红细胞压积、白细胞计数和淋巴细胞百分比下降。双硫仑的联合用药似乎增强了这些效果。用双硫仑和BEN治疗小鼠，肝脏出现严重病变。给药双硫仑后BEN血浆浓度升高，提示ALDH介导BEN在体内的快速代谢，这可能解释了给药双硫仑后BEN毒性增加的原因。我们的研究结果表明，BEN与抑制ALDH的药物或ALDH缺乏的患者合用可能导致肝损伤。
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% to 1.5% of dose) while BA excretion was unchanged. Hematocrit, white blood cells counts and %lymphocytes decreased after BEN administration. Co-administration 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 co-administration of BEN with drugs that inhibit ALDH or to patients that are ALDH deficient may cause liver damage.
登录
查看更多内容
影响因子：
5.1
作者：
Moreb, Jan S.;Ucar, Deniz;Han, Shuhong;Amory, John K.;Goldstein, Alex S.;Ostmark, Blanca;Chang, Lung-Ji
通讯作者：
Chang, Lung-Ji
DOI：
10.1007/bf01062139
发表时间：
1988-06-01
期刊：
JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS
影响因子：
--
作者：
BAILER, AJ
通讯作者：
BAILER, AJ
影响因子：
4.2
作者：
Chippendale, Thomas W. E.;Hu, Bin;Smith, David
通讯作者：
Smith, David
影响因子：
3.1
作者：
Kong, Dehe;Kotraiah, Vinayaka
通讯作者：
Kotraiah, Vinayaka
影响因子：
3.9
作者：
Stagos, Dimitrios;Chen, Ying;Vasiliou, Vasilis
通讯作者：
Vasiliou, Vasilis