**4. Conclusions**

In conclusion, the findings gained from the comparative pharmacokinetic investigations revealed there were pharmacokinetic interactions between CTE and NGTS, which may explain the integrative mechanisms of CNP and provide the experimental data and theoretical basis for further development and clinical applications of CNP. The developed LVDI-UHPLC-MS/MS method and pharmacokinetic interaction-based strategy provide a viable orientation for the compatibility investigation of herb medicines.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1999-4923/12/2/180/s1: Figure S1. The total ion current chromatogram (TIC) of CTE; the corresponding chemical composition information was reported in previous research (Chen, et al., 2014; Analyst 139, 6474–6485). Figure S2. The optimization of sample solvents for the pharmacokinetic analysis (A) and the cocktail assay (B) (*n* = 3). Figure S3. Kinetic profiles for the enzymatic turnover of CYP450-mediated probe reactions. Figure S4. Inhibition curves of the seven positive inhibitors obtained from the substrate cocktail incubation. Table S1. Multiple reaction monitoring transitions and fragmentation parameters of six standards and IS1 for PK analysis. Table S2. Multiple reaction monitoring transitions and fragmentation parameters of seven metabolites and two internal standards (IS2 and IS3) for cocktail assay. Table S3. The instrument stability of the LVDI-UHPLC-MS/MS setup. Table S4. Regression equations, linear ranges, and low limits of quantification (LLOQ) of the six standards in rat plasma for the PK study. Table S5. Intraand inter-day precisions and determination accuracies of six standards for the pharmacokinetic study. Table S6. Extract recoveries and matrix effects of six target constituents in rat plasma samples for the PK study. Table S7. Stability of the six CNP constituents in rat plasma samples for the PK study. Table S8. Plasma concentration time of the six target constituents after oral administration of CTE, NGTS, and CNP. Table S9. Regression equations, linear ranges, and LLOQs of the seven metabolites for the cocktail analysis. Table S10. Intra- and inter-day precisions and determination accuracies of the seven metabolites for cocktail analysis. Table S11. Extract recoveries and matrix effects of seven target constituents and two ISs for the cocktail analysis. Table S12. Michaelis constant (Km) determined for the enzymatic reaction of the probe substrates and the inhibition IC<sup>50</sup> values were measured for the positive inhibitors of seven CYP450s. Table S13. Responses (% control) of HSYA, GRb<sup>1</sup> , GRd, GRe, GRg<sup>1</sup> , and NGR<sup>1</sup> at their *C*max levels in the rat plasma.

**Author Contributions:** Conceptualization, P.T. and Y.J.; data curation, J.C.; funding acquisition, X.G. and Y.J.; investigation, J.C., Y.L., M.S., H.M., Y.Q., J.W., and M.L.; methodology, J.C., X.G., Y.L., M.S., and M.Z.; project administration, Y.J.; resources, P.T. and Y.J.; supervision, Y.J.; visualization, J.C.; writing—review and editing, J.C., Y.S., and Y.J. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was financially supported by National Natural Science Foundation of China (no. 81573684), Beijing Municipal Science and Technology Project (no. Z181100002218028), and National Key Technology R&D Program "New Drug Innovation" of China (no. 2018ZX09711001-008-003 and 2012ZX09103201-036).

**Conflicts of Interest:** The authors declare no conflict of interest.
