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,Xiaoyu Guo,Jinlong Wang,Yingyuan Lu,Yi Qian,Mengqiu Lu,Yuelin Song,Pengfei Tu,Yong Jiang,Mengling Shi,Mingbo Zhao,Haidong Mu

doi:10.3390/pharmaceutics12020180

Jinfeng Chen, Xiaoyu Guo + Show 10 more

Open Access

https://doi.org/10.3390/pharmaceutics12020180

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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 Rg1 (GRg1), Re (GRe), Rb1 (GRb1), and Rd (GRd); and notoginsenoside R1 (NGR1), were obtained, and the results disclosed that CNP could increase the exposure levels of HSYA, GRg1, GRe, GRb1, and NGR1 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.

Highlights

Myocardial ischemia-induced infarction is one of the leading causes of human death worldwide
It is widely accepted that the drug–drug interactions (DDIs) and herb–herb interactions (HHIs) can cause changes of pharmacokinetic profiles, which result in the possible improvement of drug efficacy and in the decrease of side effects, or vice versa [4,5]
The cytochrome p450 (CYP450) probe substrates and their corresponding metabolites for the in vitro cocktail assay were chosen according to the Food and Drug Administration (FDA) guide [14]

Summary

Introduction

Myocardial ischemia-induced infarction is one of the leading causes of human death worldwide. The benefits of either Carthamus tinctorius extract (CTE) or notoginseng total saponins (NGTS) towards myocardial ischemia injury on rats have been well defined, and more interestingly, previous studies have demonstrated that better cardio-protective effects were observed when using their combination preparation (CNP) [1,2,3]. The underlying synergetic mechanisms of CTE and NGTS combination, their pharmacokinetic (PK) interactions in particular, still remain unclear. The objective of this study was to gain insight into the synergistic actions between CTE and NGTS by determination of the pharmacokinetic profiles of six major active components from CTE and NGTS, as well as their CYP450-based synergetic mechanisms. An in vitro cocktail assay, which is an efficient and widely favored approach for CYP450-mediated HHIs, was employed to pursue the factors accounting for the different pharmacokinetic patterns before and after compatibility

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