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Development and Validation of Analytical Method for SH-1242 in the Rat and Mouse Plasma by Liquid Chromatography/Tandem Mass Spectrometry
Molecules ( IF 4.2 ) Pub Date : 2020-01-25 , DOI: 10.3390/molecules25030531
Yoo-Seong Jeong 1 , Minjeong Baek 1 , Seungbeom Lee 1, 2 , Min-Soo Kim 1 , Han-Joo Maeng 3 , Jong-Hwa Lee 4 , Young-Ger Suh 1, 2 , Suk-Jae Chung 1
Affiliation  

SH-1242, a novel inhibitor of heat shock protein 90 (HSP90), is a synthetic analog of deguelin: It was previously reported that the treatment of SH-1242 led to a strong suppression of hypoxia-mediated retinal neovascularization and vascular leakage in diabetic retinas by inhibiting the hypoxia-induced upregulation of expression in hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF). In this study, an analytical method for the quantification of SH-1242 in biological samples from rats and mice was developed/validated for application in pharmacokinetic studies. SH-1242 and deguelin, an internal standard of the assay, in plasma samples from the rodents were extracted with methanol containing 0.1% formic acid and analyzed at m/z transition values of 368.9→151.0 and 395.0→213.0, respectively. The method was validated in terms of accuracy, precision, dilution, matrix effects, recovery, and stability and shown to comply with validation guidelines when it was used in the concentration ranges of 1–1000 ng/mL for rat plasma and of 2–1000 ng/mL for mouse plasma. SH-1242 levels in plasma samples were readily determined using the developed method for up to 480 min after the intravenous administration of 0.1 mg/kg SH-1242 to rats and for up to 120 min to mice. These findings suggested that the current method was practical and reliable for pharmacokinetic studies on SH-1242 in preclinical animal species.

中文翻译:

液相色谱/串联质谱法开发和验证大鼠和小鼠血浆中 SH-1242 的分析方法

SH-1242 是一种新型的热休克蛋白 90 (HSP90) 抑制剂,是 deguelin 的合成类似物:之前有报道称,SH-1242 的治疗导致对糖尿病患者缺氧介导的视网膜新生血管形成和血管渗漏的强烈抑制通过抑制缺氧诱导的缺氧诱导因子 1α (HIF-1α) 和血管内皮生长因子 (VEGF) 的表达上调来抑制视网膜。在本研究中,开发/验证了一种量化大鼠和小鼠生物样品中 SH-1242 的分析方法,以用于药代动力学研究。用含有 0.1% 甲酸的甲醇提取啮齿类动物血浆样品中的 SH-1242 和 deguelin(该测定的内标),并分别在 368.9→151.0 和 395.0→213.0 的 m/z 转换值下进行分析。该方法在准确度、精密度、稀释度、基质效应、回收率和稳定性方面进行了验证,并且在大鼠血浆浓度范围为 1-1000 ng/mL 和 2-1000 ng/mL 的浓度范围内使用该方法时表明符合验证指南。 ng/mL 小鼠血浆。在向大鼠静脉内给予 0.1 mg/kg SH-1242 后长达 480 分钟和向小鼠给药长达 120 分钟后,使用开发的方法很容易测定血浆样品中的 SH-1242 水平。这些发现表明,目前的方法对于 SH-1242 在临床前动物物种中的药代动力学研究是实用且可靠的。在向大鼠静脉内给予 0.1 mg/kg SH-1242 后长达 480 分钟和向小鼠给药长达 120 分钟后,使用开发的方法很容易测定血浆样品中的 SH-1242 水平。这些发现表明,目前的方法对于 SH-1242 在临床前动物物种中的药代动力学研究是实用且可靠的。在向大鼠静脉内给予 0.1 mg/kg SH-1242 后长达 480 分钟和向小鼠给药长达 120 分钟后,使用开发的方法很容易测定血浆样品中的 SH-1242 水平。这些发现表明,目前的方法对于 SH-1242 在临床前动物物种中的药代动力学研究是实用且可靠的。
更新日期:2020-01-25
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