葛根芩連湯對METHOTREXATE與VALPROIC ACID藥品動力學之影響

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Title:	葛根芩連湯對METHOTREXATE與VALPROIC ACID藥品動力學之影響
Authors:	李珮端(Pei Dawn Lee Chao);侯鈺琪(Hou YuChi)
Contributors:	藥學院藥學系
Keywords:	葛根芩連湯;運送蛋白;免疫抑制劑;Methotrexate;Valproic acid;MRP
Date:	2006-12-31
Issue Date:	2009-09-01 16:25:22 (UTC+8)
Abstract:	葛根芩連湯由葛根、炙甘草、黃芩及黃連組成。Baicalin、baicalein、wogonin、puerarin、daidzin、daidzein與glycyrrhizin 為其主要成分。近代動力學研究顯示，多酚主要以sulfates、glucuronides等結合態代謝物存在於體循環中。此些結合態代謝物於生理pH下多以解離態存在。另外，glycyrrhizin口服後，主要代謝物為glycyrrhetic acid，於生理pH下亦以解離態存在。依據藥物吸收理論，此類離子型藥物必須依賴transporters進出細胞。最近的研究顯示 sulfates及 glucuronides 等之體內轉運、外排與 MRP2、MRP3 (multidrug resistance proteins) 等運送蛋白有關。 Methotrexate (MTX) 為一重要的免疫抑制劑，但治療指數非常狹窄。MTX之轉運與外排與MRP 1、MRP 2、MRP 3 與 MRP 4 等運送蛋白有關。Valproic acid (VA) 為一常用抗癲癇藥，但治療指數非常狹窄。VA之體內轉運、外排與MRP 1與 MRP 2 等運送蛋白有關。吾人推論葛根芩連湯口服後，其代謝物極可能與MTX、VA競爭MRPs而影響其轉運或外排，因此本研究擬以大白鼠為模型，探討葛根芩連湯對MTX、VA動力學之影響。本計畫擬予大白鼠分別單獨口服單一劑量與多劑量之葛根芩連湯水煎劑，並分別併服MTX、VA，定時自心臟穿刺採血，血中濃度以螢光偏極免疫測定法定量。以 WINNONLIN軟體之無室模型計算動力學參數，並以ANOVA統計組間差異。本研究預期可了解併服葛根芩連湯對MTX、VA之血中動態學之影響，對長期服用MTX、VA病患之臨床療效或安全極具參考價值。 Gergen-Chinlien Tang is composed of Gergen, honey-processed licorice, Huangchin and Huanglien. The major constituents are baicalin, baicalein, wogonin, puerarin, daidzin, daidzein and glycyrrhizin. Recent pharmacokinetic studies indicated that polyphenols were transformed into conjugated metabolites like sulfates and glucuronides that were present as anions in the bloodstream. Besides, glycyrrhetic acid, a metabolite of glycyrrhizin, was also an anion under physiological condition. According to drug absorption theory, these ionic drugs should rely on transporters for their disposition and elimination. In addition, the efflux and elimination of sulfates and glucuronides were associated with the multi-drug resistance proteins (MRP2 and MRP3). Methotrexate (MTX) is an important immunosuppressant with narrow therapeutic index. The transport of MTX was associated with MRP 1, MRP 2, MRP 3 and MRP 4. Valproic acid (VA) is a common anti-epileptic with narrow therapeutic index. The transport of MTX was associated with MRP 1 and MRP 2. We hypothesize that after cocdministration of Gergen-Chinlien Tang, the conjugated metabolites of polyphenols and glycyrrhizin would compete for MRPs with MTX and VA.and affect their dispodition and elimination. In this project, rats will be administered with MTX and VA with and without Gergen-Chinlien Tang. The blood samples will be collected via cardiopuncture and the concentrations of MTX and VA will be determined using FPIA method. The pharmacokinetic parameters will be calculates using noncompartment model of WINNONLIN and compared statistically using ANOVA. It is anticipated to measure the effects of coadministration of Gergen-Chinlien Tang on the pharmacokinetics of MTX and VA. This study will provide useful information for the efficacy and safety of MTX and VA.
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