Sorafenib has soluble epoxide hydrolase inhibitory activity, which contributes to its effect profile in vivo.
Sorafenib has soluble epoxide hydrolase inhibitory activity, which contributes to its effect profile in vivo.
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DOI：
10.1158/1535-7163.mct-09-0119
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发表时间：
2009-08
影响因子：
5.7
通讯作者：
Weiss RH
中科院分区：
文献类型：
--
作者：
Liu JY;Park SH;Morisseau C;Hwang SH;Hammock BD;Weiss RH
靶向VEGF受体的多激酶抑制剂的出现彻底改变了高血管生成性恶性肿瘤如肾细胞癌的治疗。有趣的是，几种这样的抑制剂是可商购的，并且它们各自具有不同的特定的有益和不利作用特征。在研究索拉非尼的结构时，假设该化合物对可溶性环氧化物水解酶（sEH）具有抑制作用，sEH是一种对炎症和血管疾病具有多效性作用的酶。我们现在表明，索拉非尼，而不是另一种VEGF受体靶向抑制剂舒尼替尼，是体外人sEH的有效抑制剂（KI = 17 ± 4 nM）。此外，索拉非尼引起由sEH抑制引起的氧化脂质谱的预期体内变化，这是急性炎症反应减少的证据。索拉非尼治疗可逆转脂多糖（LPS）诱导的低血压，但舒尼替尼治疗无效，这表明索拉非尼的抗炎作用至少部分与sEH抑制有关。根据索拉非尼作为sEH抑制剂的已知效力，本文提出的药代动力学研究表明，在索拉非尼的治疗剂量下，sEH将被极大地抑制。因此，索拉非尼治疗期间，sEH抑制可能有助于抑制VEGF受体和其他激酶产生有益效果。
The advent of multi-kinase inhibitors targeting the VEGF-receptor has revolutionized the treatment of highly angiogenic malignances such as renal cell carcinoma. Interestingly, several such inhibitors are commercially available, and they each possess diverse specific beneficial and adverse effect profiles. In examining the structure of sorafenib, it was hypothesized that this compound would possess inhibitory effects on the soluble epoxide hydrolase (sEH), an enzyme with pleiotropic effects on inflammation and vascular disease. We now show that sorafenib, but not another VEGF-receptor targeted inhibitor sunitinib, is a potent inhibitor of the human sEH in vitro (KI = 17 ± 4 nM). Furthermore, sorafenib causes the expected in vivo shift in oxylipid profile resulting from sEH inhibition, evidence of a reduction in the acute inflammatory response. Lipopolysaccharide (LPS)-induced hypotension was reversed with sorafenib, but not sunitinib, treatment, suggesting that sEH inhibition accounts for at least part of the anti-inflammatory effect of sorafenib. The pharmacokinetic studies presented here in light of the known potency of sorafenib as a sEH inhibitor indicate that the sEH will be largely inhibited at therapeutic doses of sorafenib. Thus it is likely that sEH inhibition contributes to the beneficial effects from the inhibition of the VEGF-receptor and other kinases during treatment with sorafenib.