PDF(Pubmed)
Abstract：
Guhong injection (GHI) has been applied in the therapy of cardio-cerebrovascular disease in clinic, but there is no report about the pharmacokinetic/pharmacodynamic (PK/PD) research on GHI treating myocardial ischemia/reperfusion (MI/R) injury in rats. In this study, eight compounds of GHI in plasma, including N-acetyl-L-glutamine (NAG), chlorogenic acid (CGA), hydroxysafflor yellow A (HSYA), p-coumaric acid ( pCA), rutin, hyperoside, kaempferol-3-O-rutinoside, and kaempferol-3-O-glucoside, were quantified by LC-MS/MS. We discovered that the values of t1/2β, k12, V2, and CL2 were larger than those of t1/2α, k21, V1, and CL1 for all compounds. The levels of four biomarkers, creatine kinase-MB (CK-MB), cardiac troponin I (cTn I), ischemia-modified albumin (IMA), and alpha-hydroxybutyrate dehydrogenase (α-HBDH) in plasma were determined by ELISA. The elevated level of these biomarkers induced by MI/R was declined to different degrees via administrating GHI and verapamil hydrochloride (positive control). The weighted regression coefficients of NAG, HSYA, CGA, and pCA in PLSR equations generated from The Unscrambler X software (version 11) were mostly minus, suggesting these four ingredients were positively correlated to the diminution of the level of four biomarkers. Emax and ED50, two parameters in PK/PD equations that were obtained by adopting Drug and Statistics software (version 3.2.6), were almost enlarged with the rise of GHI dosage. Obviously, all analytes were dominantly distributed and eliminated in the peripheral compartment with features of rapid distribution and slow elimination. With the enhancement of GHI dosage, the ingredients only filled in the central compartment if the peripheral compartment was replete. Meanwhile, high-dose of GHI generated the optimum intrinsic activity, but the affinity of compounds with receptors was the worst, which may be caused by the saturation of receptors. Among the eight analytes, NAG, HSYA, CGA, and pCA exhibited superior cardioprotection, which probably served as the pharmacodynamic substance basis of GHI in treating MI/R injury.
摘要：
谷红注射液(GHI)已在临床上用于心脑血管疾病的治疗,但目前尚无关于GHI治疗大鼠心肌缺血/再灌注(MI/R)损伤的药代动力学/药效学(PK/PD)研究报道。在这项研究中,血浆中GHI的八种化合物，包括N-乙酰基-L-谷氨酰胺（NAG），绿原酸（CGA），羟基红花黄色素A(HSYA),对香豆酸（pCA），芦丁,金丝桃苷,山奈酚-3-O-鲁丁苷，和山奈酚-3-O-葡萄糖苷，通过LC-MS/MS定量。我们发现t1/2β的值，k12、V2和CL2大于t1/2α，所有化合物的k21、V1和CL1。四种生物标志物的水平，肌酸激酶-MB（CK-MB），心肌肌钙蛋白I（cTnI），缺血修饰白蛋白（IMA），ELISA法测定血浆中α-羟丁酸脱氢酶(α-HBDH)。通过给予GHI和盐酸维拉帕米(阳性对照),由MI/R诱导的这些生物标志物的升高水平有不同程度的下降。NAG的加权回归系数，HSYA,CGA,从UnscramblerX软件（版本11）生成的PLSR方程中的pCA大多为负，表明这四种成分与四种生物标志物水平的降低呈正相关。Emax和ED50，通过采用药物和统计软件（3.2.6版）获得的PK/PD方程中的两个参数，几乎随着GHI剂量的增加而扩大。显然,所有分析物在外周区室中主要分布并消除，具有快速分布和缓慢消除的特征。随着GHI剂量的增加，如果外围隔室充满，则仅在中央隔室中填充成分。同时,高剂量的GHI产生了最佳的内在活性，但是化合物与受体的亲和力最差，这可能是由受体饱和引起的。在八种分析物中,NAG,HSYA,CGA,和pCA表现出优越的心脏保护，这可能是GHI治疗MI/R损伤的药效学物质基础。
