Studies On Drug-drug Interactions And Prediction Model Of Drugs Clinical Combination

Objective: To study the interactions of Traditional Chinese Medicine injections and the CYP2D6 drug interactions prediction models. It is to provide the reference that for the establishment of early warning methods of the safety of clinical drug interaction combination and clinical rational drug use.Methods:1. To establish RP-HPLC method. To measure the concentration of danshensu and chlorogenic acid in the plasma of rats after injection of drugs in different time. Compare the Pharmacokinetic parameters after treated with xiangdan injection, shuanghuanglian, and respectively combined with low molecular dextran and dexamethasone, then to conclude the effects of low molecular dextran and dexamethasone on Xiangdan injection and Shuanghuanglian respectively.To establish the determination method of HPLC-FD about CYP2D6 substrate specificity of dextromethorphan and its metabolites dextrorphan in rat plasma. Measuring the drug concentration of dextromethorphan and dextrorphan in rats plasma in different time after iv.. Comparison the pharmacokinetic parameters of dextromethorphan and dextrorphan with xiangdan injections and dexamethasone. And comparise the dextromethorphan's metabolic rate. Thus investigating xiangdan injections and dexamethasone on the influence of CYP2D6.2. Molecular docking with drug development software Discovery Studio 2.1, geometry-based algorithm (geometry-based) identification of protein binding site in the best molecular docking calculations. CYP2D6 on the role of the reported training set of 65 types of drugs and CYP2D6 molecular docking, and used to LigandFit and CDOCKER rate of two modules. Combined with molecular dynamics simulations to further optimize the process of molecular docking of drug molecules and protein molecules in the best binding conformation, the establishment of CYP2D6 drug interactions prediction model.The predicted outcome of 20 compounds as test set for clinical investigation of drug combination, and the findings with the model prediction. To establish the method to measure R-HPLC of baicalin determination in rat plasma. Measuring concentration of drugs after i.v in different time in rat plasma. Comparison pharmacokinetic parameters of baicalin and respectively treated with either Nimodipine or flunarizine . Testing the effects of Nimodipine or flunarizine to baicalin. and verification for the model prediction results.Results:1. Low molecular dextran has tremendous impacts on the main pharmacokinetic parameters likeα,t1/2α,CL,AUC(0-t) ,and K10 ( P<0.05),whereas not so much on the other parameters, So as Dexamethasone on t1/2α,CL,AUC(0-t), the main pharmacokinetic parameters and the other parameters of chlorogenic acid contained in Shuanghuanglian .The pharmacokinetic parameter AUC included in Dextromethorphan and dextrorphan are deeply effected by Dexamethasone and Xiangdan Both of the dextromethorphan metabolic rate had no significant effect.2. Using molecular docking software Discovery Studio 2.1 and algorithm based on geometry (geometry-based) are two protein cavity hole (320.125 ?3) binding sites for the best. Molecular Dynamics Simulation (baicalein example), CYP 2D6 subtype of Gln244, Ile297 and Ser304 can baicalin ligand oxygen atoms in the formation of one or more hydrogen bonds formed between at least 6 more strong hydrogen bond, bond length of 2.53 ~ 3.03 ?, the hydrogen bond in the CYP 2D6 and baicalin combination has an important role in the process, while the Phe120 aromatic ring and the ligand in the aromatic ring can form a strongП-ПStacking.18 kinds of competitive inhibitor of CYP2D6 were made out by studying the interaction of CYP2D6 and clinical investigations.Nimodipine and flunarizine have significant impact on baicalin drug concentration (Cmax) and the area under the curve (AUC) ,but not effect deeply the residence time (MRT),CL/F and t1/2, It demonstrates that Baicalin ,either used singly or mixed with other drugs, makes no differences to the excretion of rats. Conclusions:1. Danshensu should be monitored in clinical administration before injecting with Low molecular dextran which could bate the metabolism of Danshensu in xiangdan injections. Under dosage, Dexamethasone could promote the consumption of chlorogenic acid in Shuanghuanglian,thus speeding up the metabolism of Shuanghuanglian. Should pay attention to separate the combined clinical use, or reduce the combination to avoid adverse reactions.Xiangdan injection and dexamethasone injection do no significant inhibition and induction on the rat CYP2D6 enzyme.2. Using molecular docking and molecular dynamics simulation technique, the establishment of drug effects on CYP2D6 forecast model. It can be combined on the clinical safety of drugs and providing more information.Achieved 18 drugs who could not be combined with or need our additional attention when mixed with others in the clinical medicine ; Nimodipine and flunarizine have no competitive inhibition on CYP2D6 enzyme. The model predicted results has been proved.