| 摘要: | 三黃瀉心湯出自金匱要略，為一臨床常用方劑，包括大黃、黃連、黃芩，主治三焦實熱、心氣不足、煩躁不安、上氣不眠、吐血衄血、腹部痞滿及實熱便秘等症。本研究以高效液相層析法定量市售三黃瀉心湯濃縮製劑中黃連鹼、棕櫚鹼、小檗鹼、黃芩?、黃芩?元、漢黃芩素、大黃素、蘆薈大黃素、大黃酸、大黃酚等十種指標成分之含量，並以大鼠之血藥濃度及健康成年人之尿藥回收，比較水煎劑與濃縮散劑之生體可用率及生體相等性。 實驗結果顯示，各藥廠之產品所含成分彼此差異甚大。而經由b-glucosidase水解後，黃酮類與??類之非醣體明顯增加，顯示多酚成分多以配醣體形式存在於此些產品中。 餵予大鼠約含相等rhein劑量的水煎劑與濃縮散劑後，血清未見生物鹼，其生體可用率為零。多酚中，除rhein有原型態存在，黃酮與??成分多轉化為硫酸及葡萄糖醛酸結合態代謝物。以AUC/dose和Cmax/dose比較兩種劑型之相對生體可用率，口服濃縮散劑後，baicalein之生體可用率優於水煎劑，而aloe-emodin、wogonin、rhein、emodin與chrysophanol則是以水煎劑較佳，此六成分皆未達生體相等性。 健康受試者口服三黃瀉心湯濃縮散劑後，rhein與emodin於尿中之排除率(% of dose)優於水煎劑，其他成分則相反。兩劑型間亦未達生體相等性。各時段之排除率 (% of dose/h) 顯示各成分皆有腸肝循環現象。各成分排除半衰期(t1/2)介於2.5~14.8 h，顯示變異性頗大。個體差異亦大。 利用AAPH誘發紅血球溶血之體外試驗，三黃瀉心湯中emodin、aloe-emodin、baicalin及其經體內代謝後之sulfates/glucuronides 皆使溶血現象降低，且呈現劑量依存性。餵予大鼠三黃瀉心湯水煎劑後之血清，顯著抑制溶血現象。 此外，利用平衡透析法探討藥物之血中蛋白結合率，發現口服三黃瀉心湯後之含藥血清中各結合態代謝物之蛋白質結合率高達83.0% ~98.6%。; San-Huang-Shel-Shin-Tang (SHSST) is a popular traditional Chinese medicine formula, including Da Huang (Rhei Rhizoma), Huang Lien (Coptidis Rhizoma) and Huang Qin (Scutellariae Radix). In this study, the constituents (coptisine, palmatine, berberine, baicalin, baicalein, wogonin, emodin, aloe-emodin, rhein, chrysophanol) of SHSST extract were quantified by HPLC method. By comparing blood levels in rats and urinary recovery in humans, we attempted to evaluate the bioavailibility and bioequivalence between decoction and commercial extract of SHSST. The results showed that the contents of the bioactive constituents in commercial extract of SHSST among manufactures were quite different. The aglycones increase remarkably after hydrolyzed with b-glucosidase, indicating that polyphenols of SHSST exist mainly as glycosides. Rats were given traditional decoction and commercial extract of SHSST containing comparable dose of rhein, alkaloids were not detected in serum. Flavonoids and anthraquinones were found predominantly as sulfates and glucuronides in the bloodstream. Beside baicalein, the AUC/dose and Cmax/dose of sulfates/glucuronides of aloe-emodin, wogonin, rhein, emodin and chrysophanol after intake of commercial extract were higher than those from decoction. All consitituents of SHSST in these two dosage forms were not bioeqivalent. After ingesting SHSST commercial extract, the urinary recoveries of rhein and emodin sulfates/glucuronides were higher than decoction. Other four constituents were recovered more after ingesting decoction. The polyphenols of SHSST in these two dosage forms were essentially not bioeqivalent. All constituents demonstrated enterohepatic circulation. The excretion half-life of all constituents ranged from 2.5 to 14.8 h and the variability among individuals was large. In vitro study showed that emodin, aloe-emodin, baicalin and their conjugated metabolites inhibited AAPH-induced hemolysis in a concentration-dependent manner. Moreover, the serum obtained from rats fed SHSST significantly decreased the hemolysis. Furthermore, equilibrium dialysis method was used to evaluate protein binding of the metabolites of SHSST and the results showed they were very highly bound and ranged between 83.0% ~98.6%. |
