Garlic And Clopidogrel Drug Interactions

1ObjectivesGarlic Allium is perennial plants of the underground bulb, which rich in protein, amino acids, vitamins, fatty, polysaccharides and minerals and used as a seasoning vegetables in their daily lives. The China, India, Japan and Egypt all have the medicinal records of garlic. Many countries and nationalities are accumulated experience with garlic to prevent disease, to treat a disease, and prolong life. Thus, the garlic ancient medicinal make it become a kind of folk medicine, alternative or complementary medicine. With the deepening of the research of garlic and garlic preparation of continuous research development, the pharmacological effect of Allium got increasing attention of scholars all over the world. Now study found, garlic not only the traditional "detoxification, anti-inflammatory bactericidal" role, but also has the anti thrombosis, platelet aggregation, reducing blood lipid, vasodilation and inhibition of vascular smooth muscle cells (VSMC) proliferation effect. The pharmacological mechanism of garlic is being proved by modern science and technology. Although garlic prevention and treatment effect is in the early study, but there are many studies show that garlic has the potential pharmacological effects.Clopidogrel belongs to thienopyridine class of drugs, which is a prodrug, itself does not have the pharmacological activities. Clopidogrel metabolism to the active metabolite in the liver by the cytochrome P450enzyme and platelet adenosine diphosphate (ADP) receptor P2Y12cysteine residues form a disulfide bond. Then via irreversible blocking of the combination of ADP to its receptor to blocking the ADP inhibition of adenylate cyclase. And promote prostaglandin El stimulated adenylate cyclase-dependent vasodilators activate phosphoprotein phosphorylation, inhibition of the fibrinogen receptor GPIIb /Ⅲa activation, thereby inhibiting platelet aggregation.In clinical definition the taking conventional dose of clopidogrel can not inhibit ADP-induced platelet aggregation, clinical cardiovascular event and recurrent for clopidogrel resistance. Clopidogrel resistance was correlate to cytochrome P4503A4metabolic activity, and study found that platelet aggregation function and CYP3A4activity was significantly negative correlation. Therefor medication combined inhibition of CYP3A4or CYP3A4as substrate drugs can block the clopidogrel biological transformation to active metabolite. Long-term consumption of garlic may on hepatic drug metabolizing enzyme P450induce or inhibit, and causing their own or other drug metabolism change lead to drug interactions. This article from the pharmacodynamics and pharmacokinetics to study the garlic with clopidogrel drug interactions, to provide a theoretical basis for clinical medication.2Methods2.1Study on pharmacological of garlic and clopidogrel160NIH mouse weight (18-22g), were randomly divided into8groups, each group20(male and female each10), viz:normal control group, low, middle and high dose of garlic group, clopidogrel group, low, middle and high dose of garlic with clopidogrel group, After orally administered two weeks, measured the bleeding and clotting time in mice. SD rats were grouped according to different scheme for drug delivery, respectively, determination of platelet aggregation rate, phospholipase-I activity and blood oxygen in rats.2.2Garlic effects on clopidogrel pharmacokineticA LC-MS/MS method was developed and validated for determination of clopidogrel and its active metabolite in rat plasma. And study intragastric administration of garlic extract two weeks effect on clopidogrel pharmacokinetic in rats.2.3Garlic effect on cytochrome P450enzyme activityTo develop a LC-MS/MS method for determination of midazolam in vivo, and use midazolam as a probe drug to study intragastric administration of garlic extract two weeks effect of midazolam pharmacokinetic parameters in rats. According to midazolam pharmacokinetic parameters changes to determine the garlic extract induction or inhibition on cytochrome P450enzyme.After oral administration of garlic extract two weeks, use the Western-blot determination CYP3A protein expression in the liver, duodenum and kidney.3Results and conclusions3.1Garlic extract can prolong bleeding and clotting time in mice, garlic combination with clopidogrel can enhance the anticoagulant effect of clopidogrel. After oral administration of garlic extracts two weeks, we found that garlic extracts has an effect of inhibition platelet aggregation in rats, garlic in combination with clopidogrel can significantly improve the clopidogrel anti-platelet aggregation. Fortunately, garlic combination with clopidogrel without effect on blood routine in rats.3.2Garlic extract can be changed pharmacokinetic parameters of clopidogrel and improved clopidogrel bioavailability in rats. Compared with the normal control group, the single-dose and multi-dose clopidogrel and its active metabolite maximum plasma concentration (Cmax) and drugs-under the curve area (AUC0∞) were significantly increased.3.3Oral administration of garlic extract two weeks can significantly increase the bioavailability of midazolam in rats. This study found that oral administration of garlic extract two weeks can induced CYP3A enzyme, and Western-blot determination of CYP3A protein results further show that two weeks of oral administration of garlic extract can induce the expression of CYP3A protein in rats.