| According to the requirements of the project,the purpose of this thesis is based on drug-drug interactions technology system which mainly refers to the drug metabolism enzymes,and the law of compatibility in Tradition Chinese Medicine.The Realgar-Indigo naturalis Formula was selected as the research object which was widespread concerned with known “toxic ingredients” Chinese traditional medicine.By studying the effect of the single drug,drugdrug compatibility,effective monomer and toxic ingredients on the metabolism enzymes.We try to clarify the law of synergistic effect of Realgar-Indigo formula,reveals the scientific connotation of prescription compatibility mechanism,and provides theoretical basis for clinical rational drug use and new formula design.In this paper,the conventional toxicity evaluation technique in toxicology was used in the study of the compatibility toxicity of drugs,and the acute toxicity and subchronic toxicity were studied respectively.On quality control of realgar and influencing factors of exploration,we use the most advanced HPLC coupled to inductively coupled plasma mass spectrometry(HPLC-ICP/MS)technology,this technology can not only accurate quantitative content of soluble arsenic in realgar,and can distinguish valence state of soluble arsenic in realgar.This technique was used in the subsequent bionic extraction,in vitro compatibility and in other experiments involving the determination of soluble arsenic in realgar.In each single drug research,two compatibility of drug metabolism enzyme(CYP450 enzymes)in the study,an international recognition in vitro liver microsomal incubation method and mixed probe drugs in vivo pharmacokinetic method was adopted.The results of phase II metabolic enzymes is not presented in this paper,so it is not discussed.In this paper,we studied the effect of the single drug,drug-drug compatibility on the change of toxicity,and based on two aspects in vitro/in vivo drug interaction of the results of the study on toxicity of change reason carried on the preliminary explanation.Results showed that the acute toxicity experiment and the chronic toxicity experiments,we have observed when natural indigo and compatibility of realgar,toxicity obviously enhanced,salvia miltiorrhiza compatibility of realgar can lead less toxicity.In vitro drug interactions of bionic extraction of the experimental results show that the compatibility of indigo naturalis and realgar in intestinal alkaline environment,can significant promote the dissolution of soluble arsenic in realgar,this may be a rational explanation of toxicity enhanced.There was no obvious effect on the soluble arsenic dissolution when realgar combination with realgar,Drug interactions in the body of phase I metabolism enzyme research results show that the phase I metabolic enzymes is not the key enzyme which can influence the fate of realgar in vivo,its does not provide a reasonable explanation on the difference toxicity phenomenon.However,we have some interesting implications on the study of phase II metabolic enzyme which refers to arsenic methyltransferase.In the process of toxicity and mechanism exploration,we found that the data of realgar acute toxicity and the published reference data exist a huge difference,this is an unreasonable phenomenon,and we found the truth behind it which was the quality of realgar in the market is not homogeneous,and the quality was easy to be affected by water and temperature.According to the results of our study,we suggest that the pharmacopoeia update the test standard of realgar,and warn that the value and content of soluble arsenic in realgar should be monitored during the clinical use.Throughout this thesis,we first discovered that the realgar combination with salvia miltiorrhiza or indigo can lead significant difference of toxicity.For the first of time,we have explored the scientific connotation of Realgar-Indigo naturalis Formula from the point of view of toxicity and based on the drug-drug interactions. |
