簡介: 天然多酚類化合物常見於日常生活的食物中，近年來多酚類化合物的研究愈來愈多，而芝麻酚( sesamol )即為芝麻的酚類成分之一，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產生。芝麻酚於體外試驗證實有清除各種自由基、抗氧化、保護心血管及癌症化學預防作用。芝麻酚在體內代謝主要經由第二相反應( phase II reaction )的葡萄糖醛酸反應( glucuronidation )及硫酸化反應( sulfation )快速且大量地代謝成sesamol glucuronide與sesamol sulfate；其中葡萄糖醛酸反應為臨床藥品常見的代謝途徑，參與的酵素為尿嘧碇雙磷酸轉移酵素( UGT )。具有多種藥理活性的芝麻酚與這類相同代謝途徑的藥品併用是否出現藥物交互作用，值得進一步研究。
目的: 本研究目的在利用大白鼠動物實驗模式來探討芝麻酚於大白鼠體內動態以及它和臨床常用藥品間的交互作用。為此也將開發一套靈敏的高效液相層析法，同時定量芝麻酚與其主要代謝物sesamol glucuronide及sesamol sulfate。
方法: 在控制組實驗中，分別以靜脈注射與口服投藥方式給予不同劑量的芝麻酚以研究其藥物動態。在實驗組先給予valproic acid接著給予芝麻酚，採集血液檢品並分析芝麻酚與其主要代謝物，進一步探討其交互作用。
結果: 實驗結果已成功開發靈敏且能夠同時分析動物體液中的芝麻酚與其主要代謝物的液相層析方法。實際應用至大白鼠體內動力學研究。芝麻酚靜脈注射在劑量5~30 mg/kg呈內線性藥物動力學，口服投予在劑量15~50 mg/kg為非線性藥物動力學，其生體可用率約為10.3~35.2%。與valproic acid 交互作用結果顯示，靜脈注射併用芝麻酚與valproic acid，原型態藥物與芝麻酚代謝物血中濃度皆快速下降；而口服併用芝麻酚與valproic acid，原型態藥物皆有上升的情形，芝麻酚代謝物在一小時以後的血中濃度明顯下降。

結論: 芝麻酚在大白鼠體內會大量且快速地代謝成sesamol glucuronide與sesamol sulfate，而硫酸化代謝反應的飽和現象可能是口服投予劑量15~50 mg/kg芝麻酚為非線性藥物動力學的原因。併用同為UGTs受質的芝麻酚與valproic acid在大白鼠體內藥物交互作用之研究中，口服給藥的實驗組可以看到valproic acid最高血中濃度增加了約一倍，使血中濃度範圍高於治療濃度範圍，顯示這樣的交互作用會造成valproic acid有不良反應，甚至有發生毒性作用的可能。靜脈給藥的實驗組，反而要注意的是valproic acid血中濃度下降速度變快，會使療效作用時間減少，可能會有癲癇發作的危險。

Introduction. Natural phenolic compound is abundant in daily foods. Studies in recent years have reported that this class of compounds contains numerous beneficial health effects. Sesamol is one of the phenolic compounds in sesame. It was produced from sesamolin during the bleaching process of sesame oil with acid clay or upon roasting of sesame seed. Several effects of sesamol, including free radical scavenging, antioxidation, preventing cardiovascular diseases, and chemoprevention have been reported by previous in vitro studies.
Sesamol undergoes rapid and extensive phase II conjugation metabolism and converts to sesamol glucuronide and sesamol sulfate. Glucuronidation is mediated by uridine diphosphateglucuronosyl transferases (UGTs) and is a common metabolic pathway for various drugs. Therefore, it is of great importance to examine the pharmacokinetic interactions between sesamol and drugs that are UGTs substrates.
Purpose. The aim of this study was to investigate the pharmacokinetics and drug interactions of sesamol in SD rats. A sensitive HPLC method for simultaneous determination of sesamol and its conjugate metabolites in rat plasma was also developed for the purpose.
Method. Rats received several dose levels of sesamol intravenously and orally in the control groups. In the experiment groups, rats received sesamol after the treatment with valproic acid. Concentrations of sesamol, its metabolites and valproic acid were followed at scheduled intervals after drug administration to characterize their kinetic profiles in rats.

Result. A sensitive HPLC method for the analysis of sesamol and its major metabolites in biological fluid was developed. The method was applied successfully to pharmacokinetic studies of sesamol in rats. Following bolus injection of 5-30 mg/kg to rats, the disposition of sesamol in plasma was linear. However, nonlinear disposition was evident after oral administration of 15-50 mg/kg of sesamol with the bioavailability of 10.3-35.2%. After co-administration with valproic acid intravenously, the plasma levels of valproic acid，sesamol and its conjugate metabolites were rapidly decreased. In the oral experiment group, the plasma levels of valproic acid and sesamol were increased and the major metabolites of sesamol were decreased one hour later.
Conclusion. Sesamol undergoes rapid and extensive conjugation metabolism and converts to sesamol glucuronide and sesamol sulfate. Saturation of sulfation might be an explanation for the nonlinear pharmacokinetics of sesamol in the oral control groups. Co-administration of the UGTs substrates sesamol and valproic acid by oral route in rats resulted in a two-fold increase of the maximum concentration of valproic acid with plasma level higher than the therapeutic range. These drug interactions may produce adverse reactions, and even the toxic effects. In the bolus injection group, the interactions caused the rapid decrease of plasma valproic acid concentration to sub-therapeutic levels and may resulte in the development of epileptic seizures.

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