Tricin 7-monophosphate之製備及在大鼠中的藥物動力學研究

Abstract

Tricin （4’, 5, 7-trihydroxy-3’, 5’-dimethoxyflavone）具有抗氧化（antioxidative）、抗病毒（antiviral）、抗發炎（anti-inflammatory）、抗組織胺（antihistamic）及抗癌（cytofoxic）等多種活性。但是其水中溶解度不佳(1 mg/mL)，口服吸收率很低。為提高Tricin的生物體內利用率，本人合成了Tricin 7-monophosphate (7-TMP)作為前驅藥，並進行其口服吸收研究，口服之藥動學後，顯示7-TMP具有較好的生體可用率（21.8 %）。7-TMP在大鼠全血中37oC下一小時內幾乎全部轉化為tricin，認為其並不安定。 在大鼠口服7-TMP的研究發現，血中藥物濃度（以Tricin顯現）隨時間變化曲綫顯示有兩個最高峰（劑量為100 mg/kg、300 mg/kg和700 mg/kg），推測可能具有腸肝循環。 對大鼠口服藥物之尿液進行串聯式液相層析–固相萃取–核磁共振（LC-SPE-NMR）分析，檢測到有5個具有Tricin母體結構之葡萄酸苷代謝物，並鑒定了其中4個代謝物的結構，分別為Tricin 5,7-glcUA、Tricin 5-glcUA、Tricin 7-glcUA及Tricin 4′-glcUA。 本研究認為對Tricin做成磷酸酯鹽提高生體可用率是可行的，體外細胞實驗顯示，Tricin抑制腫瘤細胞增長的IC50為1 μM左右，而本論文中口服給藥7-TMP（100 mg/kg），大鼠血液中的Tricin濃度高於Tricin的IC50之有效時間長達5.5小時，長於iv之有效時間（2小時，100 mg/kg）

Tricin (4′,5,7-trihydroxy-3′,5′-dimethoxyflavone) has demonstrated diverse biological activities like antioxidative, antiviral, anti-inflammatory, antihistamic, and cytofoxic activities. However, its oral availability is low. To improve its bioavailability, tricin 7-monophosphate as prodrug was synthesized and its bioavailability was investigated by comparison of IV and oral administrations in Wistar male rats. The result indicated that tricin 7-monophosphate (7-TMP), detected as tricin in blood, exhibited better bioavailability (21.8 %) than the parent compound. 7-TMP is found labile in whole blood where it is completely converted to tricin in 1 hour at 37oC. Two maximum absorption peaks, detected in blood, were observed after oral administration (100, 300 and 700 mg/kg). This phenomenon implies the reabsorption of tricin through enterohepatic circulation and intestinal absorption. The metabolic profile of this prodrug via intragastrical oral administration in rat was investigated. Five metabolites were characterized in rat urine by high performance liquid chromatography–solid phase extraction–tube transfer–NMR (LC-SPE-NMR). These metabolites were glucuronide conjugates of the parent compound tricin 5, 7-glcUA, 5-glcUA, 7-glcUA, and 4′-glcUA. This study demonstrates tricin monophosphate (7-TMP) as prodrug to enhance the bioavailability of tricin is feasible. Via oral administration of 7-TMP at a dose of 100 mg/kg in rat, the blood tricin concentration could reach at least its IC50 (1 μM) against tumor cell lines over a period of 5.5 hours, relatively longer that that of iv injection (ca. 2h, 100 mg/kg).