Dihydroisosteviol在家兔體內的藥物動力學及藥效學研究

Pharmacokinetic and Pharmacodynamic Study of Dihydroisosteviol in Rabbits

郭季良(Chi-Liang Kuo)

指導教授 ： 王莉萱

臺北醫學大學/藥學院/藥學研究所/碩士(2012年)

摘要

甜菊(Stevia rebaudian)是一種菊科植物，原產於南美洲的巴西及巴拉圭。巴拉圭「Guarani」語稱甜菊為kaahee，意思是蜂蜜葉子，被當作傳統草要來使用。目前stevioside、rebaudioside A，以及其衍生物steviol、isosteviol，都被發現有降血糖的作用，其中包括：抑制糖分吸收、增加胰島素分泌及增加周邊組織對於胰島素的敏感度。
對於stevioside及其衍生物的藥物動力學及抗高血糖的作用都被大量的被研究，然而卻很少研究針對於另一個stevioside的衍生物dihydroisosteviol(DHIS)。本次研究將利用紐西蘭大白兔探討DHIS的藥物動力學以及對血糖的影響。
方法：
此實驗是一個交叉比對、成對試驗。實驗動物為健康的成年紐西蘭大白兔(八隻，平均體重2.92 kg。主要目標是探討DHIS的藥物動力學，包括靜脈及口服投與0.5、2、5 mg/kg。次要目標是觀察在口服血糖耐受度試驗中，口服投與DHIS對於血糖、血糖TAUC以及血糖IAUC的影響。而血中DHIS濃度的測量使用LC/MS/MS的方法來測量。

結論：
在本研究所開發的LC/MS/MS分析方法用於分析DHIS的血中濃度，具有相當良好的再現性、可靠度與準確性；由安定性試驗，DHIS樣品在冷凍回溫後三次之內、室溫及冷藏條件下，以及短時間(0-25小時)之內安定性良好。
靜脈投與DHIS三種不同劑量0.5、2、5 mg/kg，排除半衰期分別為556.8±587.79、512.3±117.2、760.0±515.3分鐘，清除率(CL)分別為4.18±1.87、8.0±7.5 、10.0±7.3 L/min/kg。口服投與DHIS三種不同劑量0.5、2、5 mg/kg，生體可用率(B.A.)分別為52.0±35.8%、80.02±30.53 %、72.9±46.8 %。DHIS口服投與在0.5、2、5 mg/kg的劑量下呈現線性藥物動力學。
在兔子進行口服葡萄糖耐受性試驗前(葡萄糖的劑量為3 g/kg)，口服投與DHIS會使血糖、血糖TAUC、血糖IAUC下降，並且與血中DHIS平均血中濃度呈現線性關係。但不會改變平均血糖、血糖最大值，以及血糖最大值的時間。

關鍵字

Dihydroisosteviol ； 藥物動力學

並列摘要

Stevia rebaudian is a small shrub originally grown in Brazil and Paraguay where it is known as stevia or honey leaf, Kaa-he-e. It is also generally used as traditional medicine for several hundred years in South America. The major components of Stevia rebaudian are of the leaf are stevioside (5–10% of total dry weight) and rebaudioside A (2–4%). Studies show that stevioside, reboudioside A, steviol, and isosteviol are able to decrease blood glucose by effect on glucose absorption and insulin secretion and sensitivity.
At present, the pharmacokinetic and pharmacology of stevioside, reboudioside A, steviol, and isosteviol are well established, however there are few studies about dihydroisosteviol(DHIS), a related compound of stevioside.
The present study was designed to examine the pharmacokinetic and hypoglycemic effect of DHIS in healthy rabbits in order to establish its pharmacokinetic profile and whether it has similar hypoglycemic effect with stevioside.
Methods：
This is a crossover paired design study. DHIS was dosed intravenously and orally (0.5, 2, 5 mg/kg) to New Zealand Rabbit(n=8, average body weight=2.92kg). The primary endpoint was the pharmacokinetic of DHIS, and the secondary endpoint was the effect of DHIS on level, tatol area onder curve (TAUC) and increased area under curve (IAUC) of blood glucose in rabbit during oral glucose tolerance test (OGTT). LC/MS/MS method was used to quantify the concentration of DHIS in rabbit plasma.
Conclusion：
This developedmethod has been shownto be reproducible, reliable and sensitive. DHIS sample is stable not only after three times of freeze and thaw but also at room and refrigerating temperature for 25 hours, according to the stability test.
DHIS showed linear pharmacokinetics after intravenous infusion of 0.5–5mg. Intravenous DHIS 0.5, 2, 5 mg/kg had a half-life of 556.8±587.79、512.3 ± 117.2、1126.6 ± 807.76 mins, respectively. The total clearance and steady-state volume of distribution were 4.18±1.87、8.0±7.5 、10.0±7.3 L/min/kg, respectively. The oral bioavailability of 5, 2,0.5 mg/kg DHIS were found to be 52.0±35.8、80.02±30.53 、72.9±46.8 %, respectively.
After oral administration of 0.5, 2, 5 mg/kg DHIS before oral glucose tolerance test(3 g/kg), the level, tatol area onder curve and increased area under curve (IAUC) of blood glucose were decreased linearly with average plasma concentration of DHIS. However DHIS dose not make change in Tmax、Cmax and average level of glucose.

並列關鍵字

Dihydroisosteviol ； pharmacokinetics

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