| Insomnia was a common mental disease which seriously affected people's normal life and work.In clinical,the benzodiazepine was the most frequently used anti-insomnia agent.However,they could cause a series of adverse reactions.The Chinese medicine on the treatment of insomina in the clinical application of its symptoms,reliable curative effect,less adverse reaction showed definite advantage.Ziziphi spinosae semen-Salviae miltiorrhizae was a common herb pair that has long been used in China to treat insomnia.In present study,the effect of Salviae miltiorrhizae on the pharmacokinetic and tissue distribution of Ziziphi spinosae semen was studied via LC-ESI-MS/MS method.On this basis,the compatibility mechanism of Ziziphi spinosae semen-Salviae miltiorrhizae was explored by P-glycoprotein inhibitor and monomer compatibility.The result will be used as a reference for the clinical compatibility application of Ziziphi spinosae semen-Salviae miltiorrhizae.The contents and results included,1.Developing an effective HPLC method to simultaneously determine the content of spinosin tanshinone I and tanshinone IIA in herbs.The results showed that linearity range of spinosin tanshinone I and tanshinone IIA was 20-500 ?g/mL,48-1200 ?g/mL and 48-1200 ?g/mL respectively,R2>0.999.Recovery>93%,the RSD of precision,stability and repeatability were below 2%,these results were up to the mustard of component in Traditional Chinese Medcine.2.LC-ESI-MS/MS method was established and used to determine the content of spinosin in the rat plasma and tissues.Results showed that no significant interference from endogenous substances was observed at the retention time of spinosin and IS no matter in plasma or tissues.The RSD of precision and stability were below 15%,the extraction recovery are over 89.83%,matrix effect were within 88.06%-98.33%,these results were up to the mustard of biological sample.3.Compatibility mechanism between Ziziphi spinosae semen and Salviae miltiorrhizae was explored from prospect of pharmacokinetic.Results showed that the AUC(0-t)and Cmax of spinosin increased and the V1/F decreased remarkably after the administration of Ziziphi spinosae semen-Salviae miltiorrhizae compared with that after the administration of Ziziphi spinosae semen alone.The AUC(o-t)of spinosin was increased dramatically after the co-administration of spinosin with Salviae miltiorrhizae,tanshinone I or verpamil,compared with that after the administration of spinosin alone.In addition,the V1/F value displayed a remarkable increase after the co-administration of spinosin with tanshinon IIA.Our Pharmacokinetic results suggested that tanshinone I in Salviae miltiorrhizae could promote the bioavailability of spinosin by inhibiting the effect of p-gp.4.Synergistic mechanism between Ziziphi spinosae semen and Salviae miltiorrhizae was explored from prospect of tissue distribution.The results displayed that compared with the administration of spinosin alone,the co-administration of Ziziphi spinosae semen with Salviae miltiorrhizae,the concentration of spinosin in the heart,brain and liver,spleen were obviously increased within 0.5 h and within 2-6 h respectively(P<0.001)suggesting that there were components in Salviae miltiorrhizae which could influence the tissue distribution of spinosin.The concentration of spinosin in heart,liver and brain were remarkably increased after the co-administration of spinosin with tanshinone IIA(P<0.001),compared with that after the administration of spinosin alone.However,the concentration of spinosin in the different tissues displayed a significant downward trend(P<0.05)after the co-administration of tanshinone I with spinosin.The results showed that tanshinone IIA significantly promoted the spinosin into the heart,liver and brain of the rats.That's the possible reason why Salviae miltiorrhizae increased the efficacy of Ziziphi spinosae semen on the treatment of insomina induced by blood deficiencies of the heart and liver. |
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