大蒜精油與atorvastatin藥物動力學之探討

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Title:	大蒜精油與atorvastatin藥物動力學之探討 Effects of garlic oil on the pharmacokinetics of atorvastatin in rats
Authors:	江佳容
Contributors:	營養學系碩士班
Keywords:	大蒜精油;Atorvastatin;藥物代謝酵素;藥物動力學;大鼠 Garlic oil;Atorvastatin;Drug metabolism enzyme;pharmacokinetics;Rat
Date:	2011-07-21
Issue Date:	2011-10-17 16:52:15 (UTC+8)
Publisher:	中國醫藥大學
Abstract:	近年來，由於生活型態的改變，比如飲食過量、精緻飲食、缺乏運動、壓力過大等，導致許多慢性病的發生，使得養生保健日漸受到重視。數千年來，大蒜便一直被視為是具有健康促進和疾病預防的辛香料和草藥，也是目前市場上常見保健產品之一，在美國草藥類保健產品年銷售額排名中，更位居第二名。研究顯示大蒜擁有多樣生理活性，比如降血膽固醇、降血糖、抗腫瘤、降血壓、保護肝功能、免疫調節、藥物代謝調節等，其中又以降血膽固醇和降三酸甘油脂最為人所知，所以常有大蒜保健產品和降血脂臨床用藥共同使用現象。由於大蒜中富含的多種硫化物已知會上調多種藥物代謝酵素和細胞膜轉運蛋白的轉錄作用，也有報導指出有些大蒜硫化物會直接抑制藥物代謝酵素的活性，這使得大蒜和藥物共同服用時，兩者間是否產生交互作用，影響了藥效，成為一個必須面對的議題。Atorvastatin (ATV)為臨床上常用的降膽固醇藥物，藉由抑制HMG-CoA reductase活性達到降低膽固醇的效果；在體內主要由cytochrome P450 (CYP) 3A4與UDP-glucuronosyltransferase (UGT)負責代謝，最後再透過細胞膜轉運蛋白(P-glycoprotein, P-gp)將代謝產物運出胞外。本研究因此以雄性六週齡Sprague-Dawley大鼠為實驗動物模式，先以胃管灌(i.g.)方式給予50或200 mg/kg大蒜精油(garlic oil，GO) 5天或4週，完成灌食後隔天，經口給予ATV (10 mg/kg)，隨後採集6小時間血液樣本，動物犧牲後，取肝臟和小腸組織樣本，分別作為血漿中ATV與2-OH ATV濃度變化和肝臟與小腸中藥物代謝酵素與細胞膜轉運蛋白之活性、蛋白質表現、mRNA表現分析使用。結果顯示：大蒜精油無論處理五天或四週，呈劑量關係增加ethoxyresorufin O-deethylase (CYP1A1)、pentoxyresorufin O-deethylase (CYP2B1)與UGT1A1 酵素活性(p<0.05)，在大蒜精油處理四週下，也發現testosterone 6β-hydroxylase (CYP3A) 與dextromethorphan O-demethylase (CYP2D6) 類似劑量關係增加酵素活性(p<0.05)。相反的，σ-nitrophenol hydroxylase (CYP2E1) 在五天與四週實驗中以及 diclofenac 4-hydroxylase (CYP2C)在五天實驗中皆受到大蒜精油的處理而被抑制(p<0.05)；且CYP1A1、1A2、2B1、2D1、3A1與UGT1A1的蛋白質表現結果類似於酵素活性；此外，RT-PCR結果也發現肝臟的CYP2B1、3A1與UGT1A1在大蒜精油處理下，皆呈劑量關係上調基因的表現(p<0.05)。至於肝臟中的P-gp在大蒜精油給予200 mg/kg表現下降(p<0.05)。小腸中，無論五天或四週，UGT酵素活性與蛋白質以及P-gp蛋白質皆受到大蒜精油處理而增加表現。利用LC/MS分析發現大蒜精油處理下，血漿中ATV與2-OH ATV藥物濃度呈劑量關係降低，在五天或四週處理下，血漿中ATV的最高濃度(Cmax)以及2-OH ATV，其高劑量大蒜精油組皆顯著低於控制組(p<0.05)。依上述結果推論：大蒜精油處理下，降低ATV與2-OH ATV血漿中的濃度，比如：AUC(0-6)與Cmax，主要經由調節藥物代謝酵素與膜轉運蛋白之酵素、蛋白質與mRNA的表現，因此推論大蒜精油如與ATV共同服用下，將可能與ATV的代謝產生交互作用，進而降低ATV降血膽固醇之藥效。 Due to the changes of living styles including over-eating, lacking of exercise, and consuming too much refined foods in modern society, incidence of chronic diseases increase rapidly. Garlic has been used as a culinary spice and medicinal herb for hundreds of years. It has been well demonstrated that garlic owns a diverse biological activities, such as lowering blood cholesterol, lowering blood triglycerides, lowering blood sugar, lowering blood pressure, anti-thrombosis, anti-tumorigenesis, liver protection, immunomodulation, and modulation on drug metabolism. Currently, garlic is a popular health product worldwide and the total sales were ranked the second in the herb market of the United States of America. Due to the effective hypolipidemic effect of garlic, it is possible that certain peoples will co-intake clinical drugs and garlic products, especially the elderlys and those with hyperlipidemia and chronic vascular diseases. Atorvastatin (ATV), a HMG-CoA reductase inhibitor, is the top sale hypocholesterolemic drug. It is mainly catalyzed by cytochrome P450 (CYP) 3A and UDP-glucuronosyltransferase (UGT), which increase the water solubility of ATV. Followed by the action of CYP3A and UGT, ATV metobloites are excreted out of the cells through membrane transporters, such as P-glycoprotein (P-gp). This raises a possibility whether garlic changes the pharmacokinetic parameters of ATV by modulating drug-metabolizing enzyme and transporter activities. In this study, 6 weeks-old male Sprague-Dawley rats were intragastrically (i.g.) administered 50 or 200 mg/kg GO for 5 consecutive days or thrice a week for 4 weeks. Control rats were given 1 mg/kg corn oil (vehicle). At the day 6, ATV (10 mg/kg) was given orally and bloods were withdrawn at different time intervals for 6h. Liver and small intestine were removed following sacrifice. Results indicated that GO, regardless of treating for 5 days or 4 weeks, dose-dependently increased hepatic ethoxyresorufin O-deethylase (CYP1A1), pentoxyresorufin O-deethylase (CYP2B1), and UGT1A1 activities (p<0.05). A similar dose-dependent increase of testosterone 6β-hydroxylase (CYP3A) and dextromethorphan O-demethylase (CYP 2D6) were also noted in rat livers for 4-week GO administration (p<0.05). In contrast, σ-nitrophenol hydroxylase (CYP2E1) activity in the 5-day and 4-week experiments and diclofenac 4-hydroxylase (CYP2C) activity in the 5-day experiment were decreased by GO (p<0.05). Immunoblots revealed that CYP1A1, 1A2, 2B1, 2D1, 3A1, and UGT1A1 expressions were similar to the changes of enzyme activities. Moreover, RT-PCR showed that hepatic CYP2B1, 3A1, and UGT1A1 mRNA levels were dose-dependently up-regulated by GO (p<0.05). Lower hepatic P-gp levels were resulted in rat dosed with 200 mg/kg GO (p<0.05). In the small intestine, UGT activity and protein level and P-gp protein level were increased by GO in both 5-day and 4-weeks experiments (p<0.05). By LC/MS, area under the curve (AUC0-6 h) of plasma ATV and 2-hydroxylated ATV (2-OH ATV) concentrations were dose-dependently decreased by GO (p<0.05). The maximum plasma concentration (Cmax) of ATV in 4-week treatment and of 2-OH ATV in both 5-day and 4-week treatments were significantly lower in rats administered with high dose of GO (p<0.05). In conclusion, GO decreases the plasma concentrations of ATV and 2-OH ATV, i.e. AUC0-6 h and Cmax, by modulating drug metabolizing enzymes and membrane transporter activities and/or protein and mRNA expressions. Results suggest that garlic co-administration may interact with ATV metabolism and is likely to reduce ATV blood cholesterol lowering efficacy.
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