Repeated Administration Of Resveratrol Inhibits Cytochromes P450and Drug Interaction Between Resveratrol And Antihypertensive Drugs In Humans

Human got resveratrol from the roots of mao leaves for the first time in1940, and so far scitentists have dentified72kinds of plants that contains resveratrol. In recent years, there are more and more researches on resveratrol. Resveratrol is the key factor in red wine which can dealy the progress of sclerosis of arterial congee appearance and many oronary heart disease. Resveratrol has been confirmed to have extensive pharmacological effects, such as anti-tumor, cardiovascular disease resistance, antibacterial, antiviral, anti-inflammatory, immune regulation, inhibiting platelet aggregation, anti-aging and estrogen-like activity. People have already used traditional Chinese medicines that contain resveratrol such as giant knotweed to treat or prevent of hyperlipidemia and atherosclerosis. Gradually resveratrol is used to prevent and mitigate clinical cardiovascular disease in clinical practice. And the United States has made resveratrol as a dietary supplement, and Japan also has made resveratrol as a food additive.In China there are more and more health care products that contain resveratrol.Resveratrol becomes widely used in cardiovascular protection and prevention of diseases because of the increasing of incidence of cardiovascular diseases. Researches in nearly a decade of animal experiments and clinical studies have found that resveratrol inhibition on cytochrome P450enzyme family.It is very important to clarify the influence of resveratrol on the cytochrome enzyme to predict the change of pharmacokinetic and pharmacodynamic of the drug interaction with resveratrol and cardiovascular drugs.Cytochrome P450enzyme system is a mixed function of enzyme system in liver microsomal. The activities of the cytochrome P450enzyme may change when it in contacts with all kinds of exogenous substances, and the change of the cytochrome P450enzyme activity could lead to pharmacokinetic changes in your body, resulting in the change of the efficacy of the drugs.Thus it is very important for clinical medication to study drug induction and inhibition effect on the activity of P450enzyme system. Therefore, it is of great significance to reveal the effect of resveratrol on the cytochrome family role and make a prediction for the pharmacokinetic changes with we make a combination use of the two drugs.Hypertension is the main cause of cardiovascular disease mortality, and also a key risk factor of stroke, myocardial infarction, heart failure, arterial aneurysm (e.g. aortic aneurysm), peripheral artery disease and also one of the causes of chronic kidney disease. Patients with hypertension uses many antihypertensive drugs to treat high blood pressure, and at the same time they use health care products such as resveratrol to improve the function of blood vessels, delay the progress of hypertension disease. And resveratrol may change the activity of P450enzyme, thus causing the pharmacokinetic change of antihypertensive drug metabolism when we use the two drugs together. As a result the curative effect and side effects of antihypertensive drugs will also change. Therefore, it is of great impotance to clarify antihypertensive drug pharmacokinetic changes in resveratrol and antihypertensive drug combination to find the safety and efficacy for the combination. Antihypertensive drugs include losartan, amlodipine and so on. Losartan is a kind of angiotensin receptor II inhibitor that can be used in the treatment of various kinds of high blood pressure and it is metabolized by CYP2D6. If resveratrol inhibits the activity of CYP2D6enzyme, there will be a pharmacokinetic change of losartan; Amlodipine is one of the commonly used drugs in hypertension patients. Amlodipine is mainly metabolized by CYP3A family[6,7], when CYP3A enzyme activity change can cause amlodipine pharmacokinetic changes, thus affect its efficacy and may even lead cause serious side effects.Therefore, to clarify how resveratrol influence the related commonly used antihypertensive drug metabolism could provide envidences for hypertension patients who make a combination use of resveratrol and antihypertensive drugs at the same time to increase the drug efficacy and reduce side effects.Objective: 1. Use the model to predict the probabilities of the influence of resveratrol on cytochrome P450enzymes;2. Clarify how resveratrol affect human cytochrome P450enzymes various subtypes as CYP1A2, CYP2D6, CYP2C9, CYP2C19, andCYP3A4activities in humans;3. Find the interaction of resveratrol and antihypertensive drugs in healthy subjects.Methods:1. ADMET database was used to collect all datas and ducoments about the effects of compounds on the activities of each subtype cytochrome P450enzyme research to make prediction models of each subtype of activity that based on related compounds primer type;Then we input the SMILES primer of resveratrol of each model to predict the probability influence on the activity of each subtype of enzyme;2.26healthy male subjects who aged between18and30were selected and randomly divided into experimental group and the placebo group, the volunteers in experimental group took1g resveratrol or placebo, continuously for14days. And the cocktail method was adopted. By comparing the two groups of drug blood drug concentration change and the rate of drug metabolism, we used the statistical index to determine the change of different subtypes cytochrome enzymes;3. On the basis of research2, we mesasured the concentration of resveratrol in the the after the subjects took resveratrol on the eighth day taking continuously when resveratrol reached steady state in the body of pharmacokinetic condition;4.13healthy subjects were selected. They took5mg amlodipine at the beginning of the research, after five days washout period they began to take1g resveratrol everyday for14days and then took amlodipine5mg again.We compared amlodipine pharmacokinetic parameters before and after taking resveratrol to find out the interaction of resveratrol and amlodipine; We used the data from the second chapter to find out the interaction of resveratrol and losartan.Results:1. The results of the models suggest that resveratrol could have influence on CYP1A2(91.06%), CYP2C19(80.52%), CYP3A4and CYP2C9probability is small (75.39%,70.68%), and may have no effect on CYP2D6, the probability is92.26%;2. Compared with the control group The AUC0-12, AUC0-∞, T1/2, Cmax probe drug caffeine for CYP1A2resveratrol group are significantly higher than the control group, CL/F is obviously lower than the control group; the8hours metabolic rate of probe drugs for CYP2D6and CYP2C9dextromethorphan and losartan increased obviously, there is no significant change in the pharmacokinetic parameters of the probe drug for CYP2C19and CYP3A4omeprazole and midazolam;3. Resveratrol pharmacokinetic parameters are as follows:the area under curve AUC0-12h is496.68ug/L*h, AUC0-∞is521.79ug/L*h, the peak concentration Cmax is351.22ug/L, half-life T1/2is3.31hours, Tmax Tmax was0.562hours, oral clearance CL/z2281.37L/h when it reached a steady state in human’s body;4. There is no obvios difference in amlodipine pharmacokinetic parameters have no obvious difference before and after the volunteers took resveratrol for14day. Compared with placebo group, the8hours metabolic rate of losartan in experimental group increased.Conclusions:1. Resveratrol inhibits human cytochrome enzymes CYP1A2, CYP2C9, CYP2D6, and the actibities of CYP2C19, CYP3A4did not change significantly;2. The results of the prediction models consistent with clinical trial results, indicating the models could provide certain reference basis for the research of the effects of compound on the activities of the cytochrome enzymes;3. There is no significant change in the pharmacokinetic of amlodipine after14days adminstration, while resveratrol can significantly increase the rate of metabolism of losartan;...