以大鼠模式探討橘皮素的藥物動力學及組織分佈

Abstract

近年來，存在於柑橘類水果中一種特殊的類黃酮成分－「多甲氧基黃酮 (polymethoxyflavone, PMF)」，因其具有特殊的生物活性而開始受到矚目。多甲氧基黃酮屬於黃酮類 (flavones) 的一種，其結構的特性為在基本骨架 (C6－C3－C6) 上具有兩個以上的甲氧基 (methoxy groups)，並且在C環的4號碳位置上接有一羰基。多甲氧基黃酮主要存在於柑橘屬 (citrus genus) 的植物中，尤其以果皮的部分含量最為豐富；其中，橘皮素 (tangeretin) 為一種在柑橘類果皮中頗具代表性的多甲氧基黃酮類，其化學名稱為 5,6,7,8,4’ － 五甲氧基黃酮 (5,6,7,8,4’ － pentamethoxyflavone) 。已有許多研究指出，橘皮素具有良好的生理活性，例如抗發炎、抗菌、抗癌以及降血脂等功效，但是目前對於橘皮素在生物體內生物可利用率之相關研究仍相當缺乏，故本研究之目的係以大鼠模式評估橘皮素之生物可利用性。本研究藥物動力學試驗的結果顯示，以胃管餵食大鼠50 mg/kg BW tangeretin 後，其在血液測得之 Cmax 為0.87 ± 0.33 μg/mL ， T1/2 為 342.43 ± 71.27 min；以股靜脈注射給予大鼠5 mg/kg BW tangeretin 後，其在血液測得之Cmax 為 1.11 ± 0.41 μg/mL，T1/2 為69.87 ± 15.72 min；經計算後得橘皮素之口服生物可利用率為 27.11 %，遠高於一般多元酚類化合物。推測橘皮素吸收較佳的原因可能與其分子結構帶有甲氧基而使其極性較低，因而具有較高的細胞膜穿透性有關。在大鼠體內組織分佈試驗中可發現，於胃管餵食4小時後在腸胃道即含有大量的橘皮素，尤其以胃中含量最高，佔給予劑量的20%。此外，在排除試驗部分，以胃管餵食後 0-8 hr的時間區段中有相對較高的橘皮素由尿液排出；另一方面，在胃管餵食後 8-24 hr 為橘皮素於糞便中之主要排除期。管餵48小時後約有7.5 % 橘皮素以原型態型式經由糞便排出體外；同時在 LC/MSn 的分析結果中也可觀察到有許多代謝產物產生，這些代謝物的含量與種類有待未來進一步的分析與鑑定。

There is a special group of flavonoids called polymethoxyflavones (PMFs) which is rich in citrus fruits. Since the special bioactivity has been studied extensively, this group of compounds are receiving more popularity recently. PMF is a general term for flavones bearing two or more methoxy groups on their basic benzo-γ- pyrone (C6－C3－C6) skeleton with a carbonyl group at the C4 position. PMFs exist almost exclusively in citrus plants, especially in citrus peels. Tangeretin is one of the most abundant and representative polymethoxyflavones in citrus peels, especially in tangerines and oranges, It’s also known as 5,6,7,8,4’-pentamethoxyflavone. Recent studies have shown that tangeretin exhibits anti-inflammatory, antifungal, anticancer activities and hypolipidemic effect. However, the oral bioavailability and metabolism of this compound are still lacking. The aim of this study is to investigate the bioavailability of tangeretin in Sprague-Dawley rats. In the pharmacokinetic study, after tube feeding 50mg/kg BW of tangeretin, the pharmacokinetic parameter Cmax and T1/2 were 0.87 ± 0.33 μg/mL and 342.43 ± 71.27 min, respectively. After intravenous injection of 5 mg/kg BW of tangeretin, our results showed that Cmax and T1/2 were 1.11 ± 0.41 μg/mL and 69.87 ± 15.72 min, respectively. The bioavailability of tangeretin is 27.11 % , much higher than other polyphenolic compounds. It is suggested that, the lipophilic nature of the multiple methoxy groups on the tangeretin structure, results in the lower solubility in water and higher cell membrane permeability, therefore tangeretin has higher bioavailability. In the tissue distribution study, higher concentration of tangeretin was found in the gastrointestinal tract after tube feeding 50 mg/kg BW of tangeretin for 4 hours. It was especially in stomach which contained up to 20% of dosing. Furthermore, in the excretion study, the major excretion period of tangeretin occurred 0-8 hours in urine excretion and 8-24 hours in fecal excretion after tube feeding 50 mg/kg BW of tangeretin, and 7.5% tangeretin was excreted to feces after 48 hours. On the other hand, the metabolites of tangeretin should be further studied in order to understand the health potential of tangeretin and its metabolites.