In Vivo Study Of Pharmacokinetics And Its Methodological Evaluation For Tougu Xiaotong Capsules

Knee Osteoarthritis(KOA),generally is caused by knee degeneration,trauma,overwork and other factors,while our country enters an aging society,the incidence of KOA has an increasing trend.Tougu Xiaotong prescription was Liu Xianxiang’s experience prescription,a Professor of Fujian University of Traditional Chinese medicine.The Tougu Xiaotong Capsule is one of Hospital preparation from the Second People’s Hospital of fujian province,which could improve the clinical symptoms of the patients and had good curative effect in KOA.Through the research about the methodological of Tougu Xiaotong capsule in vivo and in vitro,the pharmacokinetics of single dose,multi-dose administration,and the correlation of dose-plasma concentration in SD rats,which of methods were evaluated.On this foundation,Tougu Xiaotong Capsule were used initially in healthy volunteers in order to provide a practical guidance for the clinical application of the preparation.The method Area under the absorbability-wavelength curve(AUAWC)were used of the determination of the whole complex component in vivo and in vitro in Tougu Xiaotong capsules.The results showed that the methods of AUAWC were simple and accurate,which could be used for quality control of the capsule.The desacetyl asperulosidic acid of the effective ingredient in Morinda officinals and the target component that the retention time in the plasma sample was 23 min were used as indicator component in vitro and in vivo with the high performance liquid chromatography(HPLC)method,which had good feasibility,scientific and had better auxiliary and verification function on study in vitro.In pharmacokinetic of single dose administration study,the whole complex component of Tougu Xiaotong capsules in plasma by AUAWC and the main pharmacokinetics after oral administration were as follow:t1/2,MRT0～24 and AUC0～24 were 1.318 h,2.093 h and 14.856 mg·h·L-1,respectively.And the target component that the retention time of 23min was taken as the detection index in HPLC,the results showed that t1/2,MRT0～24 and AU0～24 were 0.761h,1.564h and 7.741g·h·L-1,respectively.Both of them conformed one-compartement model in rats,rapidly absorption,quickly elimination of the body and the 6h drug basic metabolic elimination,and revealed the metabolic situation of the overall composition of drugs and a single component in the rat respectively with good correlation and consistency.The results of multi-dose administration and its research were as follows:AUAWC was used to measure overall compositioncontent of the capsules with the single dose day for 7 days and the pharmacokinetic parameters were ti/2 of 1.101 h and AUC0-24 of 13.488 mg·h·L-1 respectively.And the result that the target component that retention time of 28 min as the detection index by HPLC were ti/2 of 0.656 h and AUC0～24 of 10.709 mg.h·L-1.The Cmax and AUCo～t cumulative ratios of two methods were 0.642,1.246 and 1.033,1,383 respectively,which suggested that there was no accumulation phenomenon of Tougu Xiaotong capsules in rats after continuous administration of 7 days,2 times a day.Simultaneously,HPLC method did not detect the target composition on the 5th and 6th day of administration,indicating that the drug administration time interval is longer or the dosage is insufficient and it is suggested that the dosage can be increased when the times of administration is constant.Research on the correlation of dose-plasma concentration and evaluation of its methods showed that the half-life of the drug was independent of the dose,and the correlation coefficients of the linear regression analysis with the method of AUAWC and HPLC were r=0.962 and r=0.957,respectively.The preliminary study on migration process of Tougu Xiaotong Capsule in rats was similar to the linear kinetic process.Combined with pre-efficacy experiments and acute toxicity in mice Indicated that 2 times or 4 times of the clinical dose was safe and reasonable,and it is recommended that the clinical dose can be increased to 2 times of the original dose.According to the results that preliminary Study on health volunteers in the body with the method of AUAWC and HPLC and its methodological evaluation,the total of drugs and individual components conformed as one-compartement model in plasma after oral 2 times the dose of Tougu Xiaotong Capsule in body.There was no significant difference between the pharmacokinetic parameters T1/2 and CL/F(P>0.05),which was consistent with the metabolism of rats in vivo.Therefore,the preliminary study of healthy volunteers in vivo further confirmed the use of 2 times in clinical dose is reasonable,feasible.