| Summary: | The combination of <i>Carthamus tinctorius</i> 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<sub>1</sub> (GRg<sub>1</sub>), Re (GRe), Rb<sub>1</sub> (GRb<sub>1</sub>), and Rd (GRd); and notoginsenoside R<sub>1</sub> (NGR<sub>1</sub>), were obtained, and the results disclosed that CNP could increase the exposure levels of HSYA, GRg<sub>1</sub>, GRe, GRb<sub>1</sub>, and NGR<sub>1</sub> at varying degrees. The in vitro cocktail assay demonstrated that CNP exhibited more potent inhibition on CYP1A2 than CTE and NGTS, and GRg<sub>1</sub>, GRb<sub>1</sub>, 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.
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