The Effect Of Ruanjiansanjie Prescription On The Pharmacokinetic Behaviors And Tissue Distribution Of Antitumor Drug

Objective:To establish reverse phase high-performance liquid chromatography methods to determine three anticancer drugs (paclitaxel,5-fluorouracil and doxorubicin) respectively, and observe the effect of RuanJianSanJie prescription (hereinafter the RuanJianSanJie prescriptions" are replaced by "RJ") on the pharmacokinetic behavior of three anticancer drugs when combined with RJ to provide reference for clinical drug combination. To establish Ehrlich ascites carcinoma (solid) tumors in animal models to study the impact of RJ on the tissue distribution of taxol (including the tumor tissue) and to explore possible attenuated mechanismof RJ.Method:1. A HPLC-UV method for determination of Paclitaxel、5-fluorouracil and doxorubicin in plasma of rats were established and validated by specificity, precision, accuracy, recovery and stability.2. The effect of RJ on the pharmacokinetic behabiors of Paclitaxel、5-fluorouracil and doxorubicin. SD rats were randomly divided into two groups:intraperitoneal injection of paclitaxel,5-fluorouracil and doxorubicin as control group, RJ combined with Paclitaxel、5-fluorouracil and doxorubicin as the experimental group, the experimental group of rats administrated RJ for7day, the last day, together with the control group, intraperitoneal injected of Paclitaxel (15mg/kg)5-fluorouracil(50mg/kg) and doxorubicin(40mg/kg), the plasma samples were abtained at set time, and with a appropriate disposal, the levels of paclitaxel、5-fluorouracil and doxorubicin was measured by HPLC method, and the pharmacokinetic parameters were calculated and compared.3. the effect of RJ on the tissue distribution of paclitaxel in tumor-bearing mice. Successfully established tumor-bearing mouse model, tumor-bearing animals were divided into experimental group and control group, the RJ prescription were administrated to the experimental group for7days, together with the control group, intraperitoneal injection of paclitaxel at set time points, anatomized heart, liver, kidney and tumor tissues, the tissue concentration of paclitaxel were detected by HPLCand comparied.Results:1. The HPLC methods for determination of the plasma concentrations of Paclitaxel、5-fluorouracil and doxorubicin were established. The absorption peak of Paclitaxel、5-fluorouracil and doxorubicin was separated without interference of impurity peak. The linear range was0.01-50μg·mL-1,0.1-100μg·mL-1,0.03-20μg·mL-1Respectively, the intra-day and inter-day orecisions were all less than15%, the recoveries were more than64%, the RSD of stability in frozen conditions were less than10%.2. Compared to the control group and the experimental group, Paclitaxel pharmacokinetic parameters, except Tmax, the experimental group i.e. Tmax=0.7500h, Tmax=1.0417h, having a significant difference, the other pharmacokinetic parameters had no significant difference. pharmacokinetic parameters of5-fluorouracil were not statistically different. pharmacokinetic parameters of doxorubicin, except for Cmax, Tmax having significant difference, other pharmacokinetic parameters had no statistical difference.3. From the view of heart, liver and kidney tissue distribution after administration of paclitaxel at peak time, heart and kidneys in control group, the paclitaxel content were more than the experimental group, while the levels of paclitaxel in tumors in experimental group were more than the control group.Conclusions:1. The established HPLC method detecting the plasma samples of paclitaxel、5-fluorouracil and doxorubicin were simple and quick, specificity, high sensitivity and suitable for the determination of paclitaxel、5-fluorouracil and doxorubicin and applicable to the determination of pharmacokinetics and tissue distribution in vivo of rodents.2. The experimental group compared with the control group, RJ can reduce the rate of absorption into the blood of taxol intraperitoneally, but did not affect the rate of removal from the blood of taxol and RJ can reduce the metabolism of taxol from liver andkindyl and increase the content of taxol in tumor tissue, suggesting RJ when combinated with taxol may have a synergistic role attenuated. RJ was also possible to increase the peak concentration of adriamycin and delay the peak, the other not parameters of pharmacokinetics of doxorubicin were not effected. RJ had no effect on the pharmacokinetic properties of5-Fu.3. Traditional Chinese medicine prescription used in combination with chemotherapy drugs, it is possible to change the pharmacokinetics and tissue distribution of chemotherapy drugs. In order to achieve the best therapeutic effect, prescription medicine should be strengthened to chemotherapy pharmacokinetics impact assessment.