College of Pharmaceutical Sciences, Zhejiang University, Zijingang Campus, No. 866 Yuhangtang Road, Hangzhou 310058, PR China.
Dali Pharmaceutical Co. Ltd., No. 118 Huanchengxi Road, Dali 671000, PR China.
J Chromatogr B Analyt Technol Biomed Life Sci. 2019 Oct 1;1128:121777. doi: 10.1016/j.jchromb.2019.121777. Epub 2019 Aug 26.
ShenMai Injection (SMI) is a traditional Chinese medicine that has been extensively applied in the treatment of coronary artery disease and tumor for many years. However, there is still lack of deep research on the behaviors of SMI in vivo. In this study, a reliable, specific, and sensitive method was developed for simultaneous determination of sixteen saponins found in SMI using liquid chromatography tandem mass spectrometry (LC-MS/MS). This method was successfully applied to investigate the pharmacokinetics, tissue distribution and excretion of sixteen active compounds after a single intravenous administration of SMI. These compounds included seven protopapaxdiol (PPD-type) ginsenosides (ginsenosides Rb, Rb, Rb, Rc, Rd, S-Rg, R-Rg), six protopapaxtriol (PPT-type) ginsenosides (notoginsenoside R, ginsenosides Re, Rf, Rg, S-Rg, R-Rg), one oleanolic acid type ginsenoside (ginsenoside Ro) and two ophiopogonins (ophiopogonin D (MD-D) and ophiopogonin D' (MD-D')). Connection of the C-20 hydroxyl group to the glycoside and the chiral configuration of C-20 might significantly impact the pharmacokinetic behaviors in vivo of ginsenosides, particularly PPD-type ginsenosides. PPD-type ginsenosides were usually eliminated slowly in serum and tissues, but S/R-Rg bearing a free hydroxyl group at C-20 exhibited quick elimination, and R-Rg underwent quicker elimination than S-Rg. The PPT-type ginsenosides, oleanolic acid type ginsenoside and ophiopogonins underwent a fast elimination from serum and tissues. There were 10 ginsenosides that could penetrate the blood-brain barrier. In contrast to other saponins, the distributions of S-Rg, R-Rg, S-Rg, R-Rg, MD-D and MD-D' in liver were higher than in kidney. Several PPD-type ginsenosides were found to have a long-term accumulation risk in some tissues, especially Rd in kidney. In the excretion study, Rg, S-Rg and MD-D were mainly excreted in a prototype and other saponins were mainly excreted in the form of metabolites. Prototypes of S-Rg, R-Rg, S-Rg, R-Rg, MD-D and MD-D' exhibited higher distribution in the liver than kidney, were excreted mainly in the feces, whereas prototypes of the remaining saponins were primarily excreted via urine. To best our knowledge, this is the first study to quantitatively evaluate the tissue distribution and excretion of SMI in rats. Our research provides novel insight into the behaviors in vivo of PPD-type ginsenosides and delivers valuable information for further drug development of SMI.
参麦注射液（SMI）是一种中药，多年来已广泛应用于治疗冠状动脉疾病和肿瘤。然而，SMI 在体内的行为仍缺乏深入研究。在这项研究中，开发了一种可靠、特异、灵敏的液相色谱-串联质谱（LC-MS/MS）法，同时测定 SMI 中十六种皂苷。该方法成功应用于单次静脉注射 SMI 后十六种活性化合物的药代动力学、组织分布和排泄研究。这些化合物包括七种原人参二醇（PPD 型）人参皂苷（人参皂苷 Rb、Rb、Rb、Rc、Rd、S-Rg、R-Rg）、六种原人参三醇（PPT 型）人参皂苷（三七皂苷 R、人参皂苷 Re、Rf、Rg、S-Rg、R-Rg）、一种齐墩果酸型人参皂苷（人参皂苷 Ro）和两种麦冬皂苷（麦冬皂苷 D（MD-D）和麦冬皂苷 D'（MD-D'））。C-20 羟基与糖苷的连接以及 C-20 的手性构型可能显著影响体内人参皂苷的药代动力学行为，特别是 PPD 型人参皂苷。PPD 型人参皂苷通常在血清和组织中缓慢消除，但 C-20 上有游离羟基的 S/R-Rg 表现出快速消除，而 R-Rg 的消除速度快于 S-Rg。PPT 型人参皂苷、齐墩果酸型人参皂苷和麦冬皂苷从血清和组织中快速消除。有 10 种人参皂苷能够穿透血脑屏障。与其他皂苷相比，S-Rg、R-Rg、S-Rg、R-Rg、MD-D 和 MD-D'在肝脏中的分布高于肾脏。一些 PPD 型人参皂苷在某些组织中具有长期蓄积风险，特别是肾脏中的 Rd。在排泄研究中，Rg、S-Rg 和 MD-D 主要以原型排泄，而其他皂苷主要以代谢物形式排泄。原型 S-Rg、R-Rg、S-Rg、R-Rg、MD-D 和 MD-D'在肝脏中的分布高于肾脏，主要通过粪便排泄，而其余皂苷的原型主要通过尿液排泄。据我们所知，这是首次定量评估 SMI 在大鼠体内的组织分布和排泄。我们的研究为 PPD 型人参皂苷的体内行为提供了新的见解，并为 SMI 的进一步药物开发提供了有价值的信息。
