| A multi-dimension HPLC/MS(MS~n) analytical model by using a combination of LC/TOF-MS and LC/ion trap MS~n was used to systemically screen and identify multiclassified components in a TCM formula Liu-Shen-Wan(LSW). Benefit from combining the accurate mass measurement of LC/TOF-MS to generate elemental compositions and the complementary multilevel structural information provided by LC/ion trap MSn, 25 components in Liu-Shen-Wan were identified in all, at the end of the analytical process, the corresponding standards were used for corroboration. All the components identified were surveyed and classified according to their medicinal materials derivation (Musk, bezoar and toad venom). To investigate the concentration of bufadienolides(BFs) in different LSW compatibility, bufadienolides were simultaneously determined by using high-performance liquid chromatography with DAD detector. As a result, the compatibility of LSW may facilitate the release of BFs.Mathematical models was used for integration of both toxicokinetics and toxicodynamics(TK-TD) to describe the relationship between BFs concentration, administration time and toxic assessment results. In the chronic toxicity test, the toxicity and accumulation of BFs was investigated to reveal the relationship between dose, time and toxicity. Through the toxicity test, the influence of LSW compatibility was investigated and the safe dose level was revealed, which will offer guide for clinical use of LSW.15 BFs, 9 isomerides, 3 deacetylated metabolites and 11 hydroxylated metabolites were screened and identified by the multi-dimension HPLC/MS(MS~n) analytical model. HPLC/TOF MS was used in the study of toxicokinetics for BFs and its metabolites. So as to the quantitative and comprehensive metabolic profile of LSW was established, which will be helpful in revealing the toxic mechanism of LSW. |
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