The anti-proliferative side effects of AEE788, a tyrosine kinase inhibitor blocking both EGF- and VEGF-receptor, are liver-size-dependent after partial hepatectomy in rats
The anti-proliferative side effects of AEE788, a tyrosine kinase inhibitor blocking both EGF- and VEGF-receptor, are liver-size-dependent after partial hepatectomy in rats
复制标题
DOI：
10.1007/s10637-010-9394-6
复制
发表时间：
2011-08-01
影响因子：
3.4
通讯作者：
Dahmen, Uta
中科院分区：
文献类型：
--
作者：
Deng, Meihong;Huang, Hai;Dahmen, Uta
背景 如前所述，酪氨酸激酶抑制剂 AEE788 阻断 EGFR 信号传导具有良好的耐受性，并且在大鼠模型中进行标准 70% 部分肝切除 (PH) 后不会抑制肝再生。然而，POW1 时 AEE788 的血清水平比未切除对照组高 3 倍。因此，我们将这些研究扩展到扩展 90%PH 的模型，以研究肝脏大小对 AEE788 代谢的作用及其对副作用、肝脏再生和肝脏重塑的潜在影响。方法 大鼠每隔一天口服50 mg/kg AEE788或溶剂，置于90%PH环境中。 PH后1、2、7和28天处死动物。我们测量了 AEE788 的血浆和肝脏水平，并评估了抗增殖副作用、肝脏再生和肝脏结构。结果 90%PH 后，AEE788 治疗未损害肝脏再生和肝脏结构。 90%PH 在治疗 1 周内引起临床相关的药物蓄积（AEE788 血清和组织水平：90%PH*> 70%PH*> 正常对照，*p < 0.05），表明药物的肝脏大小依赖性代谢。 90%PH 后的药物蓄积与治疗 1 周内的严重副作用（体重恢复延迟、腹泻、毛发生长受损）相关。结论 AEE788 治疗可能是肿瘤肝切除术后辅助治疗的潜在策略，因为肝再生不会受到损害。我们的结果表明，AEE788 的肝脏大小依赖性代谢会导致药物蓄积，进而导致严重的副作用。它要求在扩大切除术后早期进行治疗药物监测。
Background Blocking of EGFR signaling by the tyrosine kinase inhibitor AEE788 was well tolerated and did not inhibit liver regeneration after standard 70% partial hepatectomy (PH) in a rat model, as demonstrated previously. However, serum levels of AEE788 at POW1 were 3-fold higher than in the non-resected control group. Therefore, we expanded theses studies to a model of extended 90%PH to investigate the role of liver size for the metabolism of AEE788 and its potential influence on side effects, liver regeneration and liver remodeling. Method Rats treated with 50 mg/kg AEE788 or solvent every other day orally were subjected to 90%PH. Animals were sacrificed at 1, 2, 7 and 28 days after PH. We measured plasma and liver levels of AEE788 and assessed anti-proliferative side effects, liver regeneration, and liver architecture. Result Liver regeneration and liver architecture were not impaired by AEE788 treatment after 90%PH. 90%PH caused a clinically relevant drug accumulation within 1 week of treatment (AEE788 serum and tissue levels: 90%PH*> 70%PH*> normal control, *p < 0.05), suggesting a liver-size-dependent metabolism of the drug. Drug accumulation after 90%PH was associated with severe side effects (delayed body weight recovery, diarrhea, impaired hair growth) within 1 week of treatment. Conclusion Treatment with AEE788 could be a potential strategy for adjuvant treatment after oncological liver resection, as liver regeneration was not impaired. Our results suggest a liver-size-dependent metabolism of AEE788 leading to drug accumulation and subsequently to severe side effects. It calls for therapeutic drug monitoring in the early postoperative phase after extended resection.