Intravenous formulation of N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine (HET0016) for inhibition of rat brain 20-hydroxyeicosatetraenoic acid formation.
Intravenous formulation of N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine (HET0016) for inhibition of rat brain 20-hydroxyeicosatetraenoic acid formation.
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DOI：
10.1124/dmd.108.023150
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发表时间：
2008-11
期刊：
影响因子：
--
通讯作者：
Poloyac SM
中科院分区：
文献类型：
--
作者：
Mu Y;Klamerus MM;Miller TM;Rohan LC;Graham SH;Poloyac SM
N-羟基-N′-（4-正丁基-2-甲基苯基）甲脒（HET 0016）是一种有效的20-羟基二十碳四烯酸（20-HETE）抑制剂。先前的研究已经证明，在血栓栓塞性中风的大鼠模型中，给予HET 0016抑制20-HETE的脑形成并减少脑损伤。由于HET 0016在水溶液中的相对不溶性以及缺乏关于HET 0016抑制脑20-HETE形成的机制和持续时间的信息，HET 0016的剂量、浓度、神经保护作用关系的描述受到阻碍。因此，本研究的目的是开发适用于静脉内（iv）给药的HET 0016水溶性制剂，并确定体内给药后脑20-HETE抑制的时程和机制。在这项研究中，我们报告说，HET 0016是一种非竞争性抑制剂，大鼠脑20-HETE的形成，这表明组织浓度范围内的脑抑制。此外，我们证明了HET 0016与羟丙基-β-环糊精（HPβCD）的复合导致HET 0016的水溶解度从34.2 ± 31.2 μg/mL增加至452.7 ± 63.3 μg/mL。以单次静脉注射剂量（1 mg/kg）给予含复合物的制剂，将大鼠脑20-HETE浓度从289 pmol/g迅速降低至91 pmol/g。总的来说，这些数据表明，HET 0016的静脉注射制剂快速渗透大鼠脑，并显著抑制20-HETE组织浓度。这些结果将使未来的研究，以确定生物药剂学的HET 0016抑制脑缺血后的20-HETE。
N-Hydroxy-N′-(4-n-butyl-2-methylphenyl)formamidine (HET0016) is a potent inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) formation by specific cytochrome P450 (CYP) isoforms. Previous studies have demonstrated that administration of HET0016 inhibits brain formation of 20-HETE and reduces brain damage in a rat model of thromboembolic stroke. Delineation of the dose, concentration, neuroprotective effect relationship of HET0016 has been hampered by the relative insolubility of HET0016 in aqueous solutions and the lack of information concerning the mechanism and duration of HET0016 inhibition of brain 20-HETE formation. Therefore, it was the purpose of this study to develop a water soluble formulation of HET0016 suitable for intravenous (iv) administration and to determine the time course and mechanism of brain 20-HETE inhibition after in vivo dosing. In this study we report that HET0016 is a non-competitive inhibitor of rat brain 20-HETE formation, which demonstrates a tissue concentration range for brain inhibition. In addition, we demonstrate that complexation of HET0016 with hydroxypropyl-β-cyclodextrin (HPβCD) results in increased aqueous solubility of HET0016 from 34.2 ± 31.2 μg/mL to 452.7 ± 63.3 μg/mL. Administration of the complex containing formulation as a single HET0016 iv dose (1 mg/kg) rapidly reduced rat brain 20-HETE concentrations from 289 pmol/g to 91pmol/g. Collectively, these data demonstrate that the iv formulation of HET0016 rapidly penetrates the rat brain and significantly inhibits 20-HETE tissue concentrations. These results will enable future studies to determine biopharmaceutics of HET0016 for inhibition of 20-HETE after cerebral ischemia.
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影响因子：
6.1
作者：
PITHA, J;IRIE, T;NYE, JS
通讯作者：
NYE, JS
影响因子：
3.4
作者：
Govindarajan, R;Nagarsenker, MS
通讯作者：
Nagarsenker, MS
影响因子：
8.3
作者：
Omura, T;Tanaka, Y;Roman, RJ
通讯作者：
Roman, RJ
影响因子：
2
作者：
Seki, T;Wang, MH;Laniado-Schwartzman, M
通讯作者：
Laniado-Schwartzman, M
DOI：
10.1152/ajpheart.00556.2005
发表时间：
2005-11-01
影响因子：
4.8
作者：
Takeuchi, K;Renic, M;Roman, RJ
通讯作者：
Roman, RJ