**Large Volume Direct Injection Ultra-High Performance Liquid Chromatography–Tandem Mass Spectrometry-Based Comparative Pharmacokinetic Study between Single and Combinatory Uses of** *Carthamus tinctorius* **Extract and Notoginseng Total Saponins**

**Jinfeng Chen <sup>1</sup> , Xiaoyu Guo <sup>1</sup> , Yingyuan Lu <sup>1</sup> , Mengling Shi <sup>1</sup> , Haidong Mu <sup>1</sup> , Yi Qian <sup>1</sup> , Jinlong Wang <sup>1</sup> , Mengqiu Lu <sup>1</sup> , Mingbo Zhao <sup>1</sup> , Pengfei Tu 1,2, Yuelin Song 2,\* and Yong Jiang 1,\***


Received: 25 December 2019; Accepted: 17 February 2020; Published: 20 February 2020

**Abstract:** The combination of *Carthamus tinctorius* extract (CTE) and notoginseng total saponins (NGTS), namely, CNP, presents a synergistic effect on myocardial ischemia protection. Herein, comparative pharmacokinetic studies between CNP and CTE/NGTS were conducted to clarify their synergistic mechanisms. A large volume direct injection ultra-high performance liquid chromatography–tandem mass spectrometry (LVDI-UHPLC-MS/MS) platform was developed for sensitively assaying the multi-component pharmacokinetic and in vitro cocktail assay of cytochrome p450 (CYP450) before and after compatibility of CTE and NGTS. The pharmacokinetic profiles of six predominantly efficacious components of CNP, including hydroxysafflor yellow A (HSYA); ginsenosides Rg<sup>1</sup> (GRg1), Re (GRe), Rb<sup>1</sup> (GRb1), and Rd (GRd); and notoginsenoside R<sup>1</sup> (NGR1), were obtained, and the results disclosed that CNP could increase the exposure levels of HSYA, GRg1, GRe, GRb1, and NGR<sup>1</sup> at varying degrees. The in vitro cocktail assay demonstrated that CNP exhibited more potent inhibition on CYP1A2 than CTE and NGTS, and GRg1, GRb1, GRd, quercetin, kaempferol, and 6-hydroxykaempferol were found to be the major inhibitory compounds. The developed pharmacokinetic interaction-based strategy provides a viable orientation for the compatibility investigation of herb medicines.

**Keywords:** *Carthamus tinctorius* extract; notoginseng total saponins; comparative pharmacokinetic study; large volume direct injection; compatibility mechanism
