Evaluation of the cassette dosing approach for assessing the pharmacokinetics of geldanamycin analogues in mice
Evaluation of the cassette dosing approach for assessing the pharmacokinetics of geldanamycin analogues in mice
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DOI：
10.1007/s00280-004-0853-7
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发表时间：
2004-12-01
影响因子：
3
通讯作者：
Workman, P
中科院分区：
文献类型：
--
作者：
Smith, NF;Hayes, A;Workman, P
目的：目前，人们对开发苯醌安莎霉素格尔德霉素的类似物很感兴趣，这些类似物可以克服17（烯丙基氨基）-17-去甲氧基格尔德霉素（17 AAG）的局限性，17 AAG是第一个进入临床试验的已知热休克蛋白90（Hsp 90）抑制剂。进行了研究，以评估盒给药（将几种化合物同时给予一只动物）是否是评价格尔德霉素类似物高通量临床前药代动力学的合适方法。研究方法：将5种格尔德霉素类似物（17 AAG、NSC 255110、NSC 682300、NSC 683661、NSC 683663）以各5 mg/kg的组合以及以5 mg/kg和50 mg/kg的单一药剂或12.5 mg/kg的NSC 682300静脉内给予小鼠。还将化合物与小鼠肝微粒体单独孵育，并以各自15 μ M的浓度组合孵育。通过LC/MS/MS进行定量分析。通过非房室分析评价血浆和组织药代动力学参数。通过监测母体化合物的消失来评估体外代谢稳定性。结果如下：在以5 mg/kg单独给药后可检测到的化合物中，17 AAG和NSC 683661表现出非线性药代动力学。此外，与相同剂量单次给药相比，5 mg/kg卡匣给药后这些化合物的血浆曲线下面积（AUC）和半衰期更大。当以较高剂量在盒和个体给药后计算相同时间点的药代动力学参数时，与单一化合物给药相比，盒给药后三种化合物显示AUC非线性增加和清除较慢。当包括较高剂量下的所有可测量浓度时，与卡匣给药相比，个体给药后NSC 683663的半衰期长9倍。17 AAG在卡匣给药后显示出最高AUC，而NSC 683663在单一化合物给药后显示出最高AUC。除NSC 683663外，从最高到最低AUC的排序相同;然而，NSC 682300（排名第五）的个体剂量比其他化合物低4倍。肝脏和肾脏对化合物的暴露大于血浆。尽管以较低剂量给药，但NSC 682300显示出五种化合物中最高的肾脏AUC。在肾脏中，卡匣和单一化合物给药之间保持相同的排名。除NSC 682300外，体外代谢稳定性可预测血浆和肝脏中的体内药代动力学。与单独孵育相比，微粒体联合孵育后5种化合物中4种化合物的代谢程度较低，表明试剂盒中可能存在药物相互作用。然而，对于17 AAG，这可能部分是由于NSC 683661和NSC 683663代谢为该化合物。结论：虽然盒式给药在药物发现中具有优势，但由于非线性药代动力学和药物-药物相互作用，可能不适合评价格尔德霉素类似物的药代动力学。在评估其他化学型的卡匣给药适用性时，也应考虑该化合物系列中发现的问题。
Purpose: There is currently much interest in developing analogues of the benzoquinone ansamycin geldanamycin that may overcome the limitations of 17( allylamino)-17-demethoxygeldanamycin (17AAG), which is the first known inhibitor of heat shock protein 90 (Hsp90) to enter clinical trials. Studies were performed to assess whether cassette dosing, the coadministration of several compounds to a single animal, is a suitable approach to evaluate the preclinical pharmacokinetics of geldanamycin analogues in high throughput. Methods: Five geldanamycin analogues ( 17AAG, NSC 255110, NSC 682300, NSC 683661, NSC 683663) were administered intravenously to mice in combination at 5 mg/kg each and as single agents at 5 mg/kg and 50 mg/kg, or 12.5 mg/kg for NSC 682300. The compounds were also incubated with mouse liver microsomes individually and in combination at 15 muM each. Quantitative analysis was performed by LC/MS/MS. Plasma and tissue pharmacokinetic parameters were evaluated by non-compartmental analysis. In vitro metabolic stability was assessed by monitoring disappearance of the parent compound. Results: Of the compounds that were detectable following individual administration at 5 mg/kg, 17AAG and NSC 683661 exhibited nonlinear pharmacokinetics. In addition, the plasma area under the curve (AUC) and the half-life of these compounds was greater following cassette dosing at 5 mg/kg compared to single administration at the same dose. When pharmacokinetic parameters were calculated up to the same time point following cassette and individual administration at the higher dose, three of the compounds displayed non-linear increases in AUC and slower clearances following cassette compared to single compound dosing. When all measurable concentrations at the higher dose were included, the half-life of NSC 683663 was nine-fold longer following individual compared to cassette administration. 17AAG displayed the highest AUC following cassette dosing, whereas NSC 683663 displayed the highest AUC following single-compound dosing. Excluding NSC 683663, the rank order from the highest to the lowest AUC was the same; however, NSC 682300, which ranked fifth, was administered at a four-fold lower individual dose than the other compounds. Exposure of the liver and kidneys to the compounds was greater than that of plasma. Despite being administered at a lower dose, NSC 682300 displayed the highest kidney AUC of the five compounds. The same ranking was maintained between cassette and single compound dosing in the kidney. With the exception of NSC 682300, in vitro metabolic stability was predictive of in vivo pharmacokinetics in the plasma and liver. The extent of metabolism of four of the five compounds was lower following microsomal incubation in combination compared to incubation alone, suggestive of likely drug-drug interaction in the cassette. However, for 17AAG this may be partly due to metabolism of NSC 683661 and NSC 683663 to this compound. Conclusions: Whilst cassette dosing has advantages for use in drug discovery, it is probably unsuitable to evaluate the pharmacokinetics of geldanamycin analogues due to non-linear pharmacokinetics and drug-drug interaction. The issues identified for this compound series should also be considered in assessing the suitability of cassette dosing for other chemotypes.