黃連解毒湯對 Methotrexate、Cyclosporine 動力學之影響;Influence of Huang-Lian-Jie-Do-Tang on the pharmacokinetics of methotrexate and cyclosporine

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Title:	黃連解毒湯對 Methotrexate、Cyclosporine 動力學之影響;Influence of Huang-Lian-Jie-Do-Tang on the pharmacokinetics of methotrexate and cyclosporine
Authors:	陳隆彥;Lung-Yen Chen
Contributors:	中國醫藥大學：中國藥學研究所
Keywords:	黃連解毒湯;Methotrexate;Cyclosporine;Huang-Lian-Jie-Do-Tang
Date:	2008-07-15
Issue Date:	2009-08-10 18:02:15 (UTC+8)
Abstract:	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.
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