臺灣博碩士論文加值系統

黃連解毒湯由黃芩、黃連、黃柏及梔子組成。本方治一切火邪，主治實熱火毒、三焦熱盛之證。臨床上用於痢疾、黃疸、高血壓等病，為常用中藥方劑。本研究開發高效液相層析法定量黃連解毒湯水煎劑中的指標成分，包括黃芩苷 (baicalin)、黃芩苷元 (baicalein)、漢黃芩素 (wogonin)、小檗鹼 (berberine)、黃連鹼 (coptisine)、棕櫚鹼 (palmatine) 與梔子苷 (geniposide)。
胺甲葉酸 (Methotrexate, MTX) 是葉酸之抗代謝藥物，應用於多種惡性腫瘤及自體免疫疾病之治療。環孢靈 (Cyclosporine, CSP) 為一免疫抑制劑，用於治療器官移植後之排斥反應及自體免疫疾病。此二藥物治療指數狹窄。MTX 為 MRPs 和 OATs 之受質，CSP 為 P-gp 和 CYP3A4 之受質。本研究以大白鼠為模型，探討黃連解毒湯對二探針藥物 MTX 及 CSP 動力學之影響。
大白鼠單獨口服黃連解毒湯及分別併服 MTX 或 CSP 後，於特定時間點於心臟穿刺採血，MTX 和 CSP 之血中濃度以螢光偏極免疫法定量，並以WINNONLIN軟體之非室模型計算動力學參數。
研究結果顯示，併服2 g/kg、4 g/kg 黃連解毒湯造成 MTX 血藥面積分別顯著增加307 %、339 %，而平均滯留時間分別顯著延長372 %、432 %；併服 2 g/kg 黃連解毒湯則造成 CSP 血藥面積顯著降低 41 %。血藥經時變化圖顯示，黃連解毒湯抑制了 MTX 之排除，而對CSP 則是抑制了吸收。因此為確保療效與安全，服用 MTX 及 CSP 的病患最好避免併服黃連解毒湯。

Huang-Lian-Jie-Du-Tang (HLJDT), including Huang-Chin, Huang-Lien, Huang-bai and Zhi-zi, is a common Chinese prescription used for the treatments of dysentery, jaundice and hypertension. The major constituents are baicalin, baicalein, wogonin, berberine, coptisine, palmatine and geniposide. In this study, the marker constituents of HLJDT were quantified by HPLC method.
Methotrexate (MTX), a folate analogue, is used as an anticancer agent for the treatment of many cancers and immunological diseases. Cyclosporine (CSP) is a commonly used immunosuppressive agent for treating the rejection after organ transplant. Both MTX and CSP were with narrow therapeutic range. MTX is a substrate of MRPs and OATs, and CSP is a substrate of P-gp and CYP3A4. In this study, we investigated the effects of HLJDT on the pharmacokinetics of two probe drugs MTX and CSP in rats.
Rats were administered MTX or CSP with and without HLJDT. The blood samples were collected via cardiopuncture and serum MTX concentration and blood CSP concentration were determined using FPIA method. The pharmacokinetic parameters were calculated using noncompartment model of WINNONLIN and compared statistically using ANOVA.
The results showed that coadministration of 2 g/kg and 4 g/kg HLJDT significantly increased the AUC0-t of MTX by 307 % and 339 %, prolonged the MRT0-t by 372 % and 432 %, respectively, whereas 2 g/kg HLJDT significantly decreased the AUC0-t of CSP by 41 %. The facts indicated that HLJDT decreased the elimination of MTX and reduced the absorption of CSP. Patients treated with MTX or CSP should avoid the concurrent use of HLJDT in order to ensure safety and efficacy.

目錄.....................................................................................................................Ⅰ
文中圖表目錄.....................................................................................................Ⅲ
附圖目錄.............................................................................................................Ⅳ
附表目錄.............................................................................................................Ⅴ
中文摘要.............................................................................................................Ⅶ
英文摘要.............................................................................................................Ⅸ
第ㄧ章 緒言.........................................................................................................1
第二章 總論.........................................................................................................4
第一節 黃連解毒湯的簡介...........................................................................4
第二節 黃連解毒湯中成分之結構與性質...................................................8
第三節 藥物運輸蛋白…………………….................................................21
1.多重藥物抗藥性蛋白之特性.....................................................21
2. 有機陰離子運送蛋白之特性....................................................25
3. P-醣蛋白之特性.......................................................................29
第四節 胺甲葉酸 (Methotrexate) 之特性.................................................31
第五節 環孢靈 (Cyclosporine) 之特性.....................................................35
第三章 實驗材料與方法...................................................................................38
第一節 實驗材料.........................................................................................38
第二節 實驗方法.........................................................................................44
一、黃連解毒湯之製備與指標成分之定量分析.......................................44
二、黃連解毒湯於大白鼠體內對 MTX 動力學之影響…..…................48
三、黃連解毒湯於大白鼠體內對 CSP 動力學之影響…….…...............50
第四章 結果與討論...........................................................................................52
第一節 黃連解毒湯中之指標成分之定量.................................................52
第二節 黃連解毒湯於大白鼠體內對 MTX 動力學之影響......................53
第三節 黃連解毒湯於大白鼠體內對 CSP 動力學之影響........................57
第五章 結論與建議...........................................................................................60
參考文獻.............................................................................................................82









文中圖表目錄
圖一 MRPs 在腸細胞膜上表現的位置…………..……………………..22
圖二 OATs 之結構圖…………………………………….………………26
圖三 OATs 在前端腎小管的分佈………………………...……..………26
表一 MRPs 在人體的分佈……………................................................…22
表二 MRPs 之受質與抑制劑……………………………………………23
表三 MRPs在人類癌細胞之表現………….……………………………24
表四 OATs在人體的分佈及功能…………..……………………………27
表五 OATs的受質………………………..………………………………27
表六 P-gp 在人及囓齒類動物身上的基因種類………………………...29
表七 P-gp 在各個組織的表現情形……………………………………...30








附圖目錄

Fig. 1-1 HPLC chromatograms of HLJDT (upper) and standard solution (lower).………………………………………..……………………..61
Fig. 2-1 Mean (±S.E.) serum concentration-time profiles of MTX after oral administration of MTX alone (5.0 mg/kg) (●) and coadministration with 2 g/kg (○) and 4 g/kg (▼) of HLJDT (upper) and the semi-log diagram (lower)………………………….………….………………62
Fig. 2-2 Mean (±S.E.) serum concentration-time profiles of MTX after oral administration of MTX alone (5.0 mg/kg) (●) and coadministration with single dose of 2 g/kg (○) and seven doses of 2 g/kg (▼) of HLJDT (upper) and the semi-log diagram (lower).…..……..………63
Fig. 3-1 Mean (±S.E.) serum concentration-time profiles of cyclosporine after oral administration of cyclosporine alone (10 mg/kg) in consecutive treatments (n=2).………………….................................................…64
Fig. 3-2 Mean (±S.E.) serum concentration-time profiles of cyclosporine after oral administration of cyclosporine alone (2.5 mg/kg) (●) and coadministration with 2 g/kg (○) of HLJDT (upper) and the semi-log diagram (lower). ……………………………………………………65









附表目錄

Table 1-1. Intra-run and inter-run analytical precision and accuracy of geniposide.…………..…………….……………..….……….…...66
Table 1-2. Intra-run and inter-run analytical precision and accuracy of coptisine.…………………………………………….……….…..66
Table 1-3. Intra-run and inter-run analytical precision and accuracy of baicalin……..……………..……………………………...…..…..67
Table 1-4. Intra-run and inter-run analytical precision and accuracy of palmatine……………………….…….…………...……...….…...67
Table 1-5. Intra-run and inter-run analytical precision and accuracy of berberine…………………..……..…………….……….……...…68
Table 1-6. Intra-run and inter-run analytical precision and accuracy of baicalein..………………………………….…………….…….…68
Table 1-7. Intra-run and inter-run analytical precision and accuracy of wogonin………..………………………….……..…………….…69
Table 1-8. Linear regression equations for geniposide, coptisine, baicalin, palmatine, berberine, baicalein and wogonin. ……….….…….…70
Table 1-9. Recoveries (%) of geniposide, coptisine, baicalin, palmatine, berberine, baicalein and wogonin from commercial extracts of HLJDT……………………………………...………………….…71
Table 1-10. Contents (?慊/g) of geniposide, coptisine, baicalin, palmatine, berberine, baicalein and wogonin in HLJDT (n=3).…………...…72
Table 2-1. MTX serum concentration (?慆ol/L) of six rats after oral coadministration of MTX (5 mg/kg) alone.………………....…...73
Table 2-2 MTX serum concentration (?慆ol/L) of six rats after oral coadministration of MTX (5 mg/kg) with HLJDT (2 g/kg)……...73
Table 2-3 MTX serum concentration (?慆ol/L) of six rats after oral coadministration of MTX (5 mg/kg) with HLJDT (4 g/kg)……..74
Table 2-4 Pharmacokinetic parameters of MTX after oral administration of 5 mg/kg MTX alone..…..…………………….…….….……...…...74
Table 2-5 Pharmacokinetic parameters of MTX after oral coadministration of 5 mg/kg and MTX with HLJDT (2 g/kg)…...……………….…...75
Table 2-6 Pharmacokinetic parameters of MTX after oral coadministration of 5 mg/kg MTX with HLJDT (4 g/kg).………...……..…….......….75


Table 2-7 Pharmacokinetic parameters of MTX after oral administration of MTX alone (5.0 mg/kg) and coadministration with 2 g/kg (n=6) and 4 g/kg (n=6) of HLJDT.……………………………………...76
Table 2-8 MTX serum concentration (?慆ol/L) of six rats after oral coadministration of MTX (5 mg/kg) with seven doses of 2 g/kg of HLJDT.……………………………...……………..….……….…77
Table 2-9 Pharmacokinetic parameters of MTX after oral administration of MTX alone (5 mg/kg) and pretreatment with seven doses of 2 g/kg of HLJDT.….……………………………………….…………….77
Table 2-10 Pharmacokinetic parameters of MTX after oral administration of MTX alone (5.0 mg/kg) and coadministration with 2 g/kg (n=6) and pretreatment with seven doses of 2 g/kg (n=6) of HLJDT..…78
Table 3-1 Cyclosporine serum concentration (ng/mL) of six rats after oral coadministration of cyclosporine (2.5 mg/kg) alone.……….........79
Table 3-2 Cyclosporine serum concentration (ng/mL) of six rats after oral coadministration of cyclosporine (2.5 mg/kg) with HLJDT (2 g/kg).…………………………………..…..……….……….…....79
Table 3-3 Pharmacokinetic parameters of cyclosporine after oral administration of 2.5 mg/kg cyclosporine alone.…………….......80
Table 3-4 Cyclosporine serum concentration (mg/L) of six rats after oral coadministration of cyclosporine (2.5 mg/kg) with HLJDT (2 g/kg).………………………………..…....……………….….…..80
Table 3-5 Pharmacokinetic parameters of cyclosporine after oral administration of cyclosporine alone (2.5 mg/kg) and coadministration with 2 g/kg (n=6).……………………..…..…..81

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