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首页> 外文学位 >Hepatobiliary disposition of ON 01910.Na, a novel anti-cancer agent , in the isolated perfused rat liver (IPRL) model.
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Hepatobiliary disposition of ON 01910.Na, a novel anti-cancer agent , in the isolated perfused rat liver (IPRL) model.

机译：在分离的灌注大鼠肝脏（IPRL）模型中，新型抗癌药ON 01910.Na的肝胆处置。

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摘要

ON 01910.Na is a promising new, small molecule inhibitor indicated for the treatment of cancer. In this dissertation, the isolated perfused rat liver (IPRL) model was utilized for characterizing the hepatobiliary disposition of the drug. The specific goals of this research were to 1) Establish the extent of protein binding, 2) Assess the dose-linearity using the IPRL, 3) Determine the involvement of Mrp2 transporters in the biliary excretion of ON 01910.Na and 4) Establish the effect of concurrent dosing with oxaliplatin and doxorubicin on the hepatobiliary disposition. A validated HPLC method was employed for the analysis of ON 01910.Na in various matrices (perfusate, bile, rat and human plasmas). Protein binding assessments were made by way of ultrafiltration over a wide range of concentrations (1.00-250 mug/mL). ON 01910.Na was found to bind extensively in both rat and human plasmas (88.2-99.5 %). An analogous study using IPRL perfusion medium yielded similar results (87.1-98.2% bound). Upon addition of oxaliplatin (2.00 mug/mL) or doxorubicin (2.50 mug/mL), the extent of ON 01910.Na protein binding was found to decrease significantly only at the lowest concentration studied.;ON 01910.Na biliary excretion was examined at several doses (10.0-250 mug/mL). The results from these studies indicated that ON 01910.Na exhibits nonlinear pharmacokinetics. Biliary excretion was significant with more than 50% of the total administered dose recovered in the bile. Hepatic uptake was rapid with less than 10% of the Cmax remaining at tlast. Data from this group correlated extremely well with both in vivo rat data and clinical results. The use of Mrp2 deficient TR- rats enabled the study of biliary transport mechanisms. The results strongly suggest that Mrp2 transporters aid in the excretion of ON 01910.Na. Biliary clearance was reduced 2-fold in mutant rats. The hepatic uptake demonstrated a 1.5-fold decline possibly attributed to an increased expression of the sinusoidal efflux transporter, Mrp3, which has been known to occur under cholestatic conditions. A separate investigation to determine the effects of co- administration on the profile of ON 01910.Na was accomplished with oxaliplatin and doxorubicin. Addition of either interactant resulted in an increase in AUC and decrease in hepatic and biliary clearance. Oxaliplatin data correlated well with findings in previous in vivo dog work. The resultant estimates of the doxorubicin study group were comparable to those seen in TR- rats. Given that doxorubicin is a substrate for Mrp2 and data indicates that ON 01910.Na is a substrate as well, upon concurrent dosing of both drugs, a competition for the transporter may be occurring. Collectively this information allows for the possible extrapolation of ex-vivo data to in vivo and/or clinical studies as well as providing valuable information pertaining to possible treatment regimens recognizing the impact of co-administration with Mrp2 substrates.
机译：ON 01910.Na是一种有前途的新型小分子抑制剂，可用于治疗癌症。本论文利用分离的大鼠肝脏灌注模型（IPRL）来表征药物的肝胆功能。这项研究的具体目标是：1）建立蛋白质结合的程度，2）使用IPRL评估剂量线性，3）确定Mrp2转运蛋白参与ON 01910.Na胆汁排泄的活动，以及4）建立草酸铂和阿霉素同时给药对肝胆处置的影响经验证的HPLC方法用于分析各种基质（灌注液，胆汁，大鼠和人血浆）中的ON 01910.Na。通过在宽范围的浓度（1.00-250杯/毫升）中进行超滤来进行蛋白质结合评估。发现ON 01910.Na在大鼠和人血浆中广泛结合（88.2-99.5％）。使用IPRL灌注培养基的类似研究产生了相似的结果（结合率为87.1-98.2％）。加入奥沙利铂（2.00杯/毫升）或阿霉素（2.50杯/毫升）后，发现ON 01910.Na蛋白的结合程度仅在研究的最低浓度下才显着降低； ON 01910.Na胆汁排泄在几剂（10.0-250杯/毫升）。这些研究的结果表明，ON 01910.Na具有非线性的药代动力学。胆汁排泄显着，胆汁中回收的总剂量超过50％。肝脏吸收迅速，到发烧时剩余的Cmax不到10％。来自该组的数据与体内大鼠数据和临床结果都非常相关。使用缺少Mrp2的TR大鼠可以研究胆汁转运机制。结果强烈表明，Mrp2转运蛋白有助于ON 01910.Na的排泄。突变型大鼠的胆汁清除率降低了2倍。肝吸收显示减少了1.5倍，这可能归因于正弦外排转运蛋白Mrp3的表达增加，已知该表达在胆汁淤积的情况下发生。用奥沙利铂和阿霉素完成单独的研究以确定共同给药对ON 01910.Na的影响。任一种相互作用剂的添加均导致AUC增加以及肝和胆汁清除率降低。奥沙利铂数据与先前体内狗工作中的发现密切相关。阿霉素研究组的最终评估结果与TR-大鼠中观察到的结果相当。假定阿霉素是Mrp2的底物，并且数据表明ON 01910.Na也是底物，在两种药物同时给药时，可能发生转运蛋白竞争。集体地，该信息允许将离体数据可能外推至体内和/或临床研究，并提供与可能的治疗方案有关的有价值的信息，从而认识到与Mrp2底物共同施用的影响。

著录项

  • 作者

    Chun, Amy W.;

  • 作者单位

    Long Island University, The Brooklyn Center.;

  • 授予单位 Long Island University, The Brooklyn Center.;
  • 学科 Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 208 p.
  • 总页数 208
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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