Determination of the glucuronide metabolite of ON 013100, a benzylstyrylsulfone antineoplastic drug, in colon cancer cells using LC/MS/MS.
Determination of the glucuronide metabolite of ON 013100, a benzylstyrylsulfone antineoplastic drug, in colon cancer cells using LC/MS/MS.
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使用 LC/MS/MS 测定结肠癌细胞中 ON 013100（一种苯甲基苯乙烯砜抗肿瘤药物）的葡萄糖醛酸代谢物。
DOI：
10.1016/j.jpba.2012.11.022
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发表时间：
2013
影响因子：
3.4
通讯作者：
Roboz,John
中科院分区：
文献类型：
--
作者：
Cho,SoolYeon;Cosenza,StephenC;Pallela,Venkat;Panda,Gayatri;Reddy,MVRamana;Reddy,EPremkumar;Roboz,John
ON 013100，（E）-2，4，6-三甲氧基苯乙烯基-3-羟基-4-甲氧基苄基砜，是一种有效的激酶抑制剂，其磷酸盐形式在淋巴瘤和急性淋巴细胞白血病的I期临床试验中。其目的是：（a）研究药物的葡糖苷酸代谢物在两种代表性结肠癌细胞系（耐药性（科洛-205）和药物敏感性（科洛-320））中的可能存在;（B）定量用ON 013100处理后细胞中的葡糖苷酸代谢物和未改变的药物。合成了葡萄糖醛酸苷，开发并验证了用于代谢产物表征和定量的选择性LC/MS/MS方法。用ON 013100（20μg/ml）孵育1小时后，在耐药细胞中发现葡糖苷酸代谢产物（570.6 Da）。药物处理后，代谢产物的浓度从0 h的0.84μg/ml逐渐下降到6 h的0.21μg/ml，9 h时低于检测限8.0ng/ml。在药物敏感细胞中未检测到葡糖苷酸代谢产物。耐药细胞中完整的ON 013100浓度从0 h的0.41μg/ml逐渐下降到9 h的0.06μg/ml。药物敏感细胞中完整药物的相应浓度为2.88 ~ 0.94μg/ml。
ON 013100, (E)-2,4,6-trimethoxystyryl-3-hydroxy-4-methoxybenzyl sulfone, is a potent kinase inhibitor whose phosphate form is in Phase I clinical trials in lymphoma and acute lymphoid leukemia. The objectives were to: (a) investigate the possible presence of the glucuronide metabolite of the drug in two representative colon cancer cell lines, a drug resistant (colo-205) and a drug sensitive (colo-320); (b) quantify the glucuronide metabolite and the unchanged drug in the cells after treatment with ON 013100. The glucuronide was synthesized and a selective LC/MS/MS method was developed and validated for the characterization and quantification of the metabolite. The glucuronide metabolite (570.6Da) was found in the drug-resistant cells upon a 1h incubation with ON 013100 (20μg/ml). After treatment with the drug, the concentration of the metabolite gradually decreased from 0.84μg/ml at 0h through 0.21μg/ml at 6h to below detection limit of 8.0ng/ml at 9h. No glucuronide metabolite was detected in the drug-sensitive cells. The concentrations of intact ON 013100 in the drug-resistant cells gradually decreased from 0.41μg/ml (0h) to 0.06μg/ml (9h). The corresponding concentrations of the intact drug in the drug-sensitive cells were from 2.88μg/ml to 0.94μg/ml.