A mass balance and disposition study of the DNA methyltransferase inhibitor zebularine (NSC 309132) and three of its metabolites in mice
A mass balance and disposition study of the DNA methyltransferase inhibitor zebularine (NSC 309132) and three of its metabolites in mice
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DOI：
10.1158/1078-0432.ccr-06-1234
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发表时间：
2006-10-01
影响因子：
11.5
通讯作者：
Eiseman, Julie L.
中科院分区：
文献类型：
--
作者：
Beumer, Jan H.;Joseph, Erin;Eiseman, Julie L.
目的：研究DNA甲基转移酶抑制剂西布拉林（NSC 309132）在肿瘤治疗中的体内代谢命运。实验设计：雄性CD2F1小鼠静脉注射2- [C-14]斑马碱100 mg/kg。在5到1440分钟的特定时间，对小鼠实施安乐死。收集血浆、器官、胴体、尿液和粪便，测定总放射性。用高压液相色谱法分析血浆和尿液中是否含有西布拉林及其代谢物。用2- [C-14]尿苷进行了类似的实验，尿苷是斑马碱的主要代谢物。结果：总放射性、莪术碱、尿苷、尿嘧啶（各取5分钟）、二氢尿嘧啶（取15分钟）的最大血药浓度分别为462、306、33.6、21.7、11.5 μ mol/L。总放射性、斑马碱、尿嘧啶、尿嘧啶和二氢尿嘧啶迅速从血浆中消除，45分钟后，高压液相色谱法无法定量测定单个化合物。血浆数据与西布拉林依次转化为尿苷、尿嘧啶和二氢尿嘧啶的结果一致。未观察到2-嘧啶酮。在组织中观察到放射性的长时间滞留，浓度高于血浆。24小时后，尿液（剂量的30.3%）、粪便（剂量的0.4%）、笼子洗涤（剂量的7.9%）以及组织和胴体（剂量的6.1%）中给定放射性的恢复表明，高达55%的放射性以(CO2)-C-14的形式过期。比较莪术碱和尿苷的药代动力学数据表明，约40%的莪术碱剂量转化为尿苷。结论：西布拉林被广泛而迅速地代谢为内源性化合物，在观察到的浓度下不太可能产生影响。
Purpose:To elucidate the in vivo metabolic fate of zebularine (NSC 309132), a DNA methyltransferase inhibitor proposed for clinical evaluation in the treatment of cancer.Experimental Design: Male, CD2F1 mice were dosed i.v. with 100 mg/kg 2- [C-14] zebularine. At specified times between 5 and 1,440 minutes, mice were euthanized. Plasma, organs, carcass, urine, and feces were collected and assayed for total radioactivity. Plasma and urine were also analyzed for zebularine and its metabolites with a previously validated high-pressure liquid chromatography assay. A similar experiment was done with 2- [C-14] uridine, the proposed primary metabolite of zebularine.Results: Maximum plasma concentrations were 462, 306, 33.6, 21.7, and 11.5 mu mol/L for total radioactivity, zebularine, uridine, uracil (each at 5 minutes), and dihydrouracil (at 15 minutes), respectively. Total radioactivity, zebularine, uridine, uracil, and dihydrouracil were rapidly eliminated from plasma, and after 45 minutes, none of the individual compounds could be quantitated by high-pressure liquid chromatography. Plasma data were consistent with sequential conversion of zebularine to uridine, uracil, and dihydrouracil. 2-Pyrimidinone was not observed. Prolonged retention of radioactivity, at concentrations higher than in plasma, was observed in tissues. Recovery of given radioactivity in urine (30.3% of dose), feces (0.4% of dose), cage wash (7.9% of dose), and tissues and carcass (6.1% of dose) after 24 hours implied that up to 55% of radioactivity was expired as (CO2)-C-14. Comparison of zebularine and uridine pharmacokinetic data indicated that similar to 40% of the zebularine dose was converted to uridine.Conclusions: Zebularine is extensively and rapidly metabolized into endogenous compounds that are unlikely to have effects at the concentrations observed.