Laboratory of Traditional Chinese Medicine Research and Development of Hebei Province, Institute of Traditional Chinese Medicine, Chengde Medical University, Chengde 067000, China.
Molecules. 2023 Oct 9;28(19):6995. doi: 10.3390/molecules28196995.
In previous studies, we reported compound (5-chloro--(4-oxo-2,2-dipropyl-3,4-dihydro-2-benzo[][1,3]oxazin-6-yl)-1-indole-2-carboxamide) as a novel PYGB inhibitor, and found that it had better anti-ischemic brain injury activity. In this study, we established and validated a novel UHPLC-MS/MS method for the quantitative determination of compound in plasma, then applied the method to study the pharmacokinetic parameters and brain tissue distribution of compound in SD (Sprague-Dawley) rats after intravenous administration. The experimental results showed that the method met the validation requirements set by the US FDA in terms of linearity, accuracy, precision, and stability. The validated method was then used for pharmacokinetic studies in rat plasma, and it was found that compound exhibited linear pharmacokinetic characteristics when administered in the dose range of 0.8-3.2 mg/kg. Finally, we also conducted a brief preliminary investigation of the brain tissue distribution of compound in rats after injection and found that the brain tissue concentrations at 0.25 h and 2 h of administration were 440 ± 19.1 ng/kg and 111 ± 23.9 ng/kg, respectively. Additionally, the C/C ratio was 0.112 ± 0.0185 and 0.112 ± 0.0292, respectively. These results indicated that compound was able to cross the blood-brain barrier. This study provides important support for the application of compound in ischemic brain injury diseases.
在之前的研究中，我们报道了化合物（5-氯-（4-氧代-2,2-二丙基-3,4-二氢-2-苯并[][1,3]恶嗪-6-基）-1-吲哚-2-甲酰胺）是一种新型的 PYGB 抑制剂，并发现它具有更好的抗缺血性脑损伤活性。在这项研究中，我们建立并验证了一种新的 UHPLC-MS/MS 方法，用于定量测定血浆中的化合物，然后应用该方法研究了化合物在静脉给药后 SD（Sprague-Dawley）大鼠中的药代动力学参数和脑组织分布。实验结果表明，该方法在线性、准确性、精密度和稳定性方面均符合美国 FDA 设定的验证要求。验证后的方法随后用于大鼠血浆中的药代动力学研究，结果发现，化合物在 0.8-3.2 mg/kg 的剂量范围内表现出线性药代动力学特征。最后，我们还对化合物在大鼠体内的脑组织分布进行了初步探讨，发现给药后 0.25 h 和 2 h 时脑组织浓度分别为 440±19.1ng/kg 和 111±23.9ng/kg，C/C 比值分别为 0.112±0.0185 和 0.112±0.0292。这些结果表明，化合物能够穿过血脑屏障。这项研究为化合物在缺血性脑损伤疾病中的应用提供了重要支持。
