| Danshen is the dried root of Salvia miltiorrhiza Bunge(Labiatae).Tanshinone IIA(TsIIA) is a derivative of the phenanthrenequinone type isolated from Salvia miltiorrhiza Bunge.It is the lipid-soluble effective component with the most content in Danshen and possesses wide pharmacological activities such as anti-oxidation, anti-tumor,dilating coronary artery,preventing angina pectoris and myocardial infarction,and protecting the brain against damage by ischemia perfusion or by ischemia-hypoxia.Studies on pharmacokinetics of TslIA have recently been reported, but no study concerning the phacmacokinetic characteristics of TslIA in brain has been reported.Since brain is one of the target organs of its pharmacological action, studying related pharmacokinetic characteristics of TslIA,especially that in brain and investigating the behavior of TslIA permeating the blood-brain barrier have great meaning for the overall understanding of its pharmacological action and clinical application.In this thesis,an HPLC method was developed and validated to measure the concentration of TslIA in plasma and brain.The method had a linear range from 0.0498 to 7.12 mg/L in plasma and a linear range from 0.022 to 2.37 mg/L in brain. The limits of quantitation(LOQs) in plasma and brain were 0.0498 and 0.022 mg/L, respectively,and the limits of detection(LODs) were 0.0255 and 0.0166 mg/L, respectively.The intra-day and inter-day RSD were less than 10.2%.The method has been applied for related pharmacokinetic study of TslIA.The results indicated that the concentration of TslIA in rat plasma reached the peak value of 0.13±0.03 mg/L at 2.261±0.334 h after oral administration of TsIIA.The concentration-time curve was fitted to two-compartment model.The distribution half life(t1/2α) was 1.226 h and the elimination half life(t1/2β) was 4.951 h.These pharmacokinetic parameters suggested that the distribution of TsIIA in vivo was rapid,but the elimination of TsIIA was relatively slow after oral administration.The concentration-time curve of TsIIA was fitted to two-compartment model after intravenous administration.The distribution half life(t1/2α) was 24.63 min～29.19 min and the elimination half life(t1/2β) was 106.82 min～207.74 min.These results indicated that the distribution of TsIIA was fast and the elimination of TsIIA was slow after intravenous administration.The absolute bioavailability of TsIIA was below 1.6%.These findings revealed that the absorption of TsIIA was poor,so it is not appropriate for oral use.The first-pass metabolism could be avoided and the bioavailability of TslIA would be raised when it is made into preparation for intravenous use.Besides,nonlinear pharmacokinetics was observed for TslIA in rats when the dosage of TslIA for intravenous administration was increased from 7.6 to 15.2 mg/kg in the research.The pharmacokinetic diffrences of TsIIA in plasma and brain were investigated after intravenous administration of TsIIA and the tanshinone extract of Salvia miltiorrhiza Bunge,respectively.The results revealed that TsIIA readily penetrated the blood-brain barrier,eliminated slowly in brain and could stay in the brain for a long time.Other components in the tanshinone extract of Salvia miltiorrhiza Bunge would affect the pharmacokinetics of TsIIA in plasma a little but not obviously.Compared with the group which was administrated with TsIIA only,the pharmacokinetics of TsIIA in brain was greatly changed in the group which was administrated with the tanshinone extract of Salvia miltiorrhiza Bunge.Accordingly,the concentration and AUC value of TsIIA were significantly increased and the time to achieve the maximum concentration was prolonged.The results suggested that the components in the tanshinone extract of Salvia miltiorrhiza Bunge might enhance the penetration of Ts II A across the blood-brain barrier.These results provided some references for reasonable clinic application of Ts II A.It is important for the clinical indication and understanding of the synergism oftanshinone compounds. |
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