| 摘要: | 大黃、大黃素之代謝動力學 及其對環孢靈動力學之影響 研究生 張珮樺 中國醫藥學院 藥物化學研究所 摘要 北大黃為蓼科植物掌葉大黃Rheum palmatum L.的乾燥根及根莖。■■成分包括蘆薈大黃素(aloe-emodin)、大黃酸 (rhein) 、大黃素(emodin)、大黃酚 (chrysophanol)為大黃的活性成分。本研究利用高效液相層析法，以梯度沖提，同時分析水煎劑中蘆薈大黃素、大黃酸、大黃素、大黃酚及其配醣體之含量。結果顯示水煎劑中游離■■的含量以rhein最多，其次為emodin、aloe-emodin、chrysophanol；除了rhein主要以游離態存在之外，aloe-emodin、emodin、chrysophanol大多以結合態配醣體存在。大黃酒製後總■■及游離■■均減量，對配醣體含量之影響則為減少(aloe-emodin及emodin)、增加(rhein)，或不影響(chrysophanol)。 大白鼠口服生大黃、熟大黃水煎劑(5 g/kg)後，以心臟穿刺採血，分別以β-glucuronidase及sulfates■解後，利用高效液相層析法定量鼠體內自由態及結合態代謝物之血中濃度，並比較■■成分動力學之改變。兩種大黃水煎劑口服後，除了rhein有原形吸收外 (14 %)，各■■成分主要以sulfates (44~58 %)與glucuronides (37~56 %) 結合態代謝物存在於體循環中。大黃酒製後■■成分之口服吸收較佳。 環孢靈為一常用之免疫抑制劑，但治療指數極低，任何會影響其血中濃度之因素，都有可能使生命受到威脅。本研究以大白鼠為模型，探討emodin及大黃、虎杖水煎劑對環孢靈動力學之影響。血中之環孢靈濃度以螢光偏極免疫分析法 (Fluorescence Polarization Immunoassay，FPIA) 定量。結果顯示環孢靈併服emodin或大黃、虎杖水煎劑後，平均血藥面積分別顯著低於控制組達69.5 %、65.0 %及75.3 %。另外比較併服大黃水煎劑對環孢靈靜脈(0.8 mg/kg)給藥之影響，結果顯示併服大黃水煎劑後，環孢靈平均血藥面積增加102.8 % ，平均全身清除率降低40.6 %。此等結果可推測大黃水煎劑對口服環孢靈生可用率降低的影響主要發生在吸收部位，此降低吸收的影響遠超過其降低全身清除率之作用。因此建議接受環孢靈治療之病人應盡量避免併用含大黃、虎杖、emodin成分之中藥製劑，以免造成器官排斥，以確保環孢靈之療效與安全。; Metabolic Pharmacokinetics of Rheum palmatum and Emodin and Their Effects on Cyclosporine Pharmacokinetics Pei-Hua Chang Graduate Institute of Pharmaceutical Chemistry China Medical College Abstract Rhubarb is the dry root and root stock of Rheum palmatum L. (Polygonaceae). Anthraquinones including aloe-emodin, rhein, emodin and chrysophanol are the active constituents of rhubarb. This study used HPLC gradient elution to simultaneously determine aloe-emodin, rhein, emodin and chrysophanol and their glycosides in decoctions of rhubarb prior to and after wine processing. The results indicated that rhein is the heighiest content of four anthraquinones, followed by emodin, aloe-emodin and chrysophanol in rhubarb. Only rhein occurs mostly as free form, others occurs mostly as glycosides. Both total and free anthraquinones were decreased after wine processing, whereas rhein glycosides increased and chrysophanol glycosides remained substantially unchanged. Furthermore, rats were administered with various decoctions equivalent to 5 g/kg after overnight fast. Blood was withdrawn via cardiopuncture and assayed by HPLC method prior to and after emzymatic hydrolysis with sulfatase and β-glucuronidase, respectively. A simple, sensitive, and accurate HPLC method was developed for the determination of these anthraquinones and their conjugated metabolites simultaneously. The results showed that only rhein existed in part as free form (14 %), all anthraquinones were found predominantly as sulfates (44~58 %) and glucuronides (37~56 %) in bloodstream. Cyclosporine is a commonly used immunosuppressive agent with narrow therapeutic range. Any factor influencing its blood level might threaten life. In this study, the rats were given cyclosporine alone and with emodin, decoctions of Da Huang or Hu Zhang, respectively. The blood cyclosporine concentration was determined by fluorescence polarization immunoassay. The results showed that the mean AUC of cyclosporine were decreased by 69.5 %, 65.0 % and 75.3 % after oral coadministration of cyclosporine with emodin, Da Huang and Hu Zhang, respectively. However, when coadministration of cyclosporine (i.v.) with Da Huang decoction (p.o); the AUC was increased by 102.8 % and the Clearance was decreased by 40.6 %. Therefore, it could be presumed that the lowering effect of Da Huang decoction in bioavailability occurred mainly at absorption site, and that was much more marked than the lowering in Clearance. We suggested that for the sake of efficacy and safety, the coadministration of Da Huang, Hu Zhang or herbs containing emodin with cyclosporine should be avoided. |
