以大鼠模式探討 5,7,3’,4’–tetramethoxyflavone 的藥物動力學及組織分佈

Study on the Pharmacokinetics and Tissue Distribution of 5,7,3’,4’-tetramethoxyflavone in Rat

蔡佳玲(Chia-Ling Tsai)

指導教授 ： 孫璐西

國立臺灣大學/生物資源暨農學院/食品科技研究所/碩士(2013年)

https://doi.org/10.6342/NTU.2013.00779

摘要

多甲氧基黃酮 (Polymethoxyflavones, PMFs) 為類黃酮的一種，在 C6-C3-C6 基本的骨架上接有兩個以上的甲氧取代基。許多研究證實此類物質具有和未被甲基化的黃酮相似的活性，如抗癌、抗病毒等，並且生物可利用率高於未被甲基化的黃酮。 5,7,3’,4’-Tetramethoxyflavone (TMF) 被發現存在於Kaempferia parviflora (黑薑) 和 Orthosiphon spicatus (貓鬚草) 等植物中。已有文獻指出 TMF具有抗真菌、抗發炎等活性。但目前對於 TMF生物可利用率之相關研究仍相當地少。本研究以大鼠模式來研究 TMF 之藥物動力學及組織分佈。藥物動力學結果顯示，以靜脈注射給予大鼠 TMF (5 mg/kg, i.v.)後，在血漿中測得之 Cmax為 1.54±0.62 μg/mL，T1/2為62.85±27.92 分鐘；管餵給予大鼠 TMF (50 mg/kg BW) 後，Cmax為 0.79±0.30μg/mL，Tmax 為190±24.50 分鐘，T1/2為273±90.2 分鐘；經計算得到 TMF的口服生物可利用率為 14.3 %，比起未被甲基化黃酮高，推測是由於結構上的甲氧基降低極性，促使膜穿透率及代謝穩定性提高。
在分佈試驗部分，於管餵 TMF (50 mg/kg BW) 2 小時後測定各個臟器中TMF的含量，以腸胃道的胃含量最高，佔餵食劑量之 43 % 以上；在管餵 8小時後則以盲腸、大腸及直腸含量較多。此外，管餵 TMF (50 mg/kg BW) 2 小時後，在腦中也可偵測到其存在。而測定組織臟器中3’-hydroxy-5,7,4’-trimethoxyflavone (M1)、4’-hydroxy-5,7,3’-trimethoxyflavone (M4)及5-hydroxy-7,3’,4’-trimethoxyflavo ne (M5) 等代謝物之含量，發現 TMF 以轉變為M1加M4代謝物為主，且以12小時為最高的時間點， 於12 小時M1+M4在所有組織臟器總量，佔管餵劑量百分比的57.47 %。
排除試驗結果顯示，在胃管餵食 TMF (50 mg/kg BW) 後的12-24小時內有較高量的 TMF由糞便排除， TMF於糞便中排除總量佔餵食劑量0.8121% 。而在尿液中以4-12小時為TMF主要排除期，佔總餵食劑量百分比0.0496%。利用 M4 、M5兩種代謝物標準品，以及酵素水解方式定量，得到尿液中 M1+M4及M5代謝物排除量佔管餵劑量百分比為50 %。並從尿液中也發現不同形式的代謝物，代謝物含量及結構有待未來進一步之探討。

關鍵字

5,7,3’,4’–tetramethoxyflavone ； 多甲氧基黃酮 ； 口服生物可利用率 ； 藥物動力學

並列摘要

Polymethoxyflavones (PMFs), a special group of flavonoids with two or more methoxy groups on benzene ring (C6-C3-C6), have demonstrated many physiological activities similar to unmethylated flavones, but with higher bioavailability. 5,7,3’,4’-Tetramethoxyflavone (TMF) is one of the major polymethoxyflavones present in Kaempferia parviflora and Orthosiphon spicatus. Several studies have shown that TMF has many bioactivities such as anti-allergic activity, antifungal and anti-inflammatory effects, but the oral bioavailability of TMF is not clear so far. Thus, the purpose of this study is to investigate the bioavailability of TMF in Sprague-Dawley rats. In pharmacokinetic study, Cmax and T1/2 were determined to be 1.54±0.62 μg/mL and 62.85±27.92 minutes, respectively, after intravenous injection of 5 mg/kg BW of TMF. After tube feeding 50 mg/kg BW of TMF, the pharmacokinetic parameters of Cmax, Tmax and T1/2 were 0.79±0.30 μg/mL, 190±24.50 minute and 273±90.2 minutes, respectively. The bioavailability of TMF is 14.3%, much higher than some flavonoids. The lipophilicity methoxy of groups on TMF structure gave higher cell membrane permeability and improved metabolic stability, thus higher oral bioavailability was observed.
In tissue distribution study, higher concentration of TMF were found in gastrointestinal tracts after tube feeding 50 mg/kg BW for 2 hour and 4 hours, stomach was shown to possess the highest content of TMF in 2 hours which contained up to 43% of dosing. TMF was also detected in brain. 3’-hydroxy-5,7,4’-trimethoxyflavone (M1), 4’-hydroxy-5,7,3’-trimethoxyflavone (M4) and 5-hydroxy-7,3’,4’-trimethoxyflavone (M5) were found to exhibit the tissue among the three metabolites of TMF, after feeding TMF. M1 plus M4 were also observed of 12 hours, after tube feeding 50 mg/kg BW TMF, M1 plus M4 reached the hightest concentration in all tissue containing up to 57 % of dosing.
In excretion study, the main fecal excretion of TMF was found during 12-24 hours, containing about 0.8121 % of dosing, after tube feeding 50 mg/kg BW TMF. The main urinary excretion of TMF was found during 4-12 hours, TMF content in urine was only 0.0496% of dosing. The metabolites M1 plus M4 are the major metabolites in urine, the total amount of M1, M4 and M5 can reach 50 % of dosing. There are other possible urinary metabolites of TMF which should be further identified and quantified.

並列關鍵字

5,7,3’,4’-tetramethoxyflavone (TMF) ； Metabolites ； oral bioavailability ； Pharmacokinetics ； polymethoxyflavones(PMFs)

參考文獻

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