Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern.
Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern.
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DOI：
10.1016/j.prostaglandins.2015.06.005
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发表时间：
2015-09
影响因子：
2.9
通讯作者：
Schebb NH
中科院分区：
文献类型：
--
作者：
Ostermann AI;Herbers J;Willenberg I;Chen R;Hwang SH;Greite R;Morisseau C;Gueler F;Hammock BD;Schebb NH
来自多不饱和脂肪酸（PUFA）的环氧化物是有效的脂质介质。通过阻断可溶性环氧化物水解酶（sEH）来体内稳定这些环氧化物导致抗炎、镇痛和血压正常的作用。因此，sEH抑制剂（sEHi）是一类有前途的新药物。本文中，我们表征了市售有效sEHi 1-三氟甲氧基苯基-3-（1-丙酰基哌啶-4-基）脲（TPPU）的药代动力学（PK）和药效学性质。细胞培养研究表明，它的高吸收和代谢稳定性。大鼠饮用水给药后（含0.2%PEG 400的0.2、1和5 mg TPPU/L），TPPU的血药浓度在给药期间呈剂量依赖性增加，8天后几乎达到稳态。TPPU被发现在所有的组织测试。组织中的亚油酸环氧化物/二醇比率呈剂量依赖性增加，表明显著的sEH抑制。总体而言，TPPU与饮用水一起给药导致全身分布以及高水平，因此使慢性sEH抑制研究成为可能。
Epoxides from polyunsaturated fatty acids (PUFAs) are potent lipid mediators. In vivo stabilization of these epoxides by blockade of the soluble epoxide hydrolase (sEH) leads to anti-inflammatory, analgesic and normotensive effects. Therefore, sEH inhibitors (sEHi) are a promising new class of drugs. Herein, we characterized pharmacokinetic (PK) and pharmacodynamic properties of a commercially available potent sEHi 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU). Cell culture studies suggest its high absorption and metabolic stability. Following administration in drinking water to rats (0.2, 1, and 5 mg TPPU/L with 0.2% PEG400), TPPU’s blood concentration increased dose dependently within the treatment period to reach an almost steady state after 8 days. TPPU was found in all the tissues tested. The linoleic epoxide/diol ratios in the tissues were dose dependently increased, indicating significant sEH inhibition. Overall, administration of TPPU with the drinking water led to systemic distribution as well as high levels and thusmakes chronic sEH inhibition studies possible.