芝麻酚在大白鼠之口服生物可利用率

Oral Bioavailability of Sesamol in Rats

謝欣玲(Hsin-Ling Hsieh)

指導教授 ： 孫璐西

共同指導教授 ： 蔡東湖

國立臺灣大學/生物資源暨農學院/食品科技研究所/碩士(2005年)

https://doi.org/10.6342/NTU.2005.02718

摘要

芝麻酚 (sesamol) 為芝麻油中一種抗氧化物質，其主要是在芝麻油脫色的步驟或芝麻種子炒焙的過程中，由 sesamolin 所產生。本實驗之目的為利用微透析技術採樣及傳統之全血採樣方法，探討芝麻酚在大白鼠之藥物動力學及口服生物可利用率。
本實驗中，利用微透析技術採樣，並建立一快速而檢測靈敏度高之高效液相層析分析方法，測定透析液中芝麻酚含量，以探討非結合態芝麻酚於大白鼠體內之藥物動力學。微透析技術是大白鼠於麻醉狀態下將微透析探針同時置入其頸靜脈、膽管、腦部之紋狀體及肝臟中葉，以進行採樣，另由股靜脈注射給藥。高效液相層析之分離管柱是採用逆向碳 18 管柱 (4.6 mm i.d. × 250 mm, 4 μm particle size)，移動相是由 acetonitrile 及 10 mM 磷酸二氫鈉水溶液以體積比 35:65 所組成，再以磷酸調整 pH 值至 4.0，流速為 1 ml/min，紫外光偵測波長設定在 294 nm。結果顯示，由股靜脈注射給予 30 mg/kg 之芝麻酚後，芝麻酚在血液、膽汁、腦部及肝臟之最高濃度 (Cmax) 分別為 8.36 ± 1.47、2.65 ± 0.63、3.33 ± 0.55 及 1.17 ± 0.14 μg/ml；藥物半衰期 (t1/2) 分別為 7.51 ± 1.01、10.3 ± 4.0、6.49 ± 2.18 及 6.49 ± 1.14 min；藥物濃度對時間曲線下面積 (AUC) 分別為 75.3 ± 18.2、44.1 ± 8.3、44.0 ± 7.0 及 11.4 ± 7.6 min μg/ml。分布係數可由組織所測得之 AUC 與血液之 AUC 之比值計算而得，芝麻酚之膽血分布係數 (AUCbile/AUCblood) 為 0.602 ± 0.126，腦血分布係數 (AUCbrain/AUCblood) 為 0.603 ± 0.120，而肝血分布係數 (AUCliver/AUCblood) 為 0.140 ± 0.074。此結果亦指出芝麻酚可通過血腦障壁 (BBB)，並且會由膽汁排泄。口服生物可利用率為藥物給予後，到達體循環之原型藥與給藥劑量之比例。芝麻酚分別以胃管強迫餵食及靜脈注射給予後，於特定之時間點進行採血，再利用高效液相層析分析方法，測定血漿中總芝麻酚濃度。高效液相層析之條件與為透析採樣時相同，但移動相之 pH 值修改為 4.15。在以胃管強迫餵食 30、100 和 300 mg/kg 以及由靜脈注射給予 30 mg/kg 之劑量後，芝麻酚在血漿中最高濃度 (Cmax) 分別為 11.2 ± 6.2、22.2 ± 7.3、60.5 ± 14.0 及 38.8 ± 16.8 μg/ml；藥物半衰期 (t1/2) 分別為 9.43 ± 4.33、13.2 ± 4.9、11.1 ± 2.4 及 15.3 ± 5.8 min；血漿濃度對時間曲線下面積 (AUC) 分別為 110 ± 70、443 ± 150、1140 ± 360 及 343 ± 96 min μg/ml。此結果顯示，芝麻酚於血漿中之濃度下降迅速；在 30 – 300 mg/kg 之劑量範圍內，芝麻酚之藥物半衰期與劑量無關，而 AUC 則隨劑量增加成比例增加，推測在此劑量範圍內芝麻酚呈線性藥物動力學。芝麻酚在大鼠之口服生物可利用率為 34.8%；另外，芝麻酚在血漿中之蛋白質結合率為 82.8%。

關鍵字

芝麻酚 ； 口服生物可利用率

並列摘要

Sesamol (benzo[1,3]dioxol-5-ol) has been generally regarded as the main antioxidative component in sesame oil. It was produced from sesamolin during the bleaching process of sesame oil with acid clay or upon roasting of sesame seed. The purpose of this study was to investigate the oral bioavailability and pharmacokinetic characteristics of sesamol in rats, both microdialysis and traditional blood sampling methods were employed. We developed a rapid and sensitive high performance liquid chromatographic method coupled with microdialysis system to measure the unbound sesamol from various biological fluids. Multiple microdialysis probes were concurrently inserted into the jugular vein, bile duct, brain striatum and the median lobe of liver of each anesthetized rat for sampling after sesamol administration (30 mg/kg) through the femoral vein. Separation of the unbound sesamol from various biological fluids was performed by a reversed phase C18 column (4.6 mm i.d. × 250 mm, 4 μm particle size). The mobile phase consisted of acetonitrile-10 mM sodium dihydrogen phosphate buffer (35:65, v/v) (adjusted to pH 4.0 with phosphoric acid) at a flow rate of 1 ml/min. The UV detector wavelength was set at 294 nm. The results showed that the maximum concentration of sesamol in blood, bile, brain and liver were 8.36 ± 1.47, 2.65 ± 0.63, 3.33 ± 0.55 and 1.17 ± 0.14 μg/ml; the half-lives were 7.51 ± 1.01, 10.3 ± 4.0, 6.49 ± 2.18 and 6.49 ± 1.14 min; the area under the concentration versus time curves (AUCs) were 75.3 ± 18.2, 44.1 ± 8.3, 44.0 ± 7.0 and 11.4 ± 7.6 min μg/ml, respectively. The extent of systemic unbound sesamol distributed to bile, brain and liver, calculated as AUCbile/AUCblood, AUCbrain/AUCblood and AUCliver/AUCblood were 0.602 ± 0.126, 0.603 ± 0.120 and 0.140 ± 0.074. In addition, the results indicated that sesamol penetrates the blood-brain barrier (BBB) and goes through hepatobiliary excretion. The oral bioavailability is defined as the fraction of the dose which reaches the systemic circulation as intact drug. Blood samples were collected at various time intervals after sesamol administration and then assayed by a validated HPLC system. The separation of sesamol in rat plasma was performed under the similar HPLC condition as in the microdialysis samples except the mobile phase was adjusted to pH 4.15. After sesamol administration (30, 100 and 300 mg/kg, p.o. and 30 mg/kg, i.v.), the maximum concentration of sesamol were 11.2 ± 6.2, 22.2 ± 7.3, 60.5 ± 14.0 and 38.8 ± 16.8 μg/ml; the half-lives were 9.43 ± 4.33, 13.2 ± 4.9, 11.1 ± 2.4 and 15.3 ± 5.8 min; AUCs were 110 ± 70, 443 ± 150, 1140 ± 360 and 343 ± 96 min μg/ml, respectively. The results showed that the concentrations of sesamol declined rapidly and the elimination half-lives did not relate to the dosage ranges. AUCs presented dose dependent manner. These results suggested that sesamol appears a linear pharmacokinetic phenomenon. The oral bioavailability of sesamol was 34.8% in rats. The protein binding ratio of sesamol was 82.8% in rat plasma.

並列關鍵字

sesamol ； oral bioavailability

參考文獻

bioavailability of tea and tea polyphenols. Mutat Res 523-4: 201-8.

Yamada H. 1993. Protective effects of sesamin against liver damage

Budowski P. 1950. Sesamol oil. III. Antioxidant properties of sesamol. J

Amer Oil Chem Soc 27: 264-7.

stability of physiological parameters during sustained anesthesia in