中西藥物併用之交互作用研究- 芍藥對抗癲癇藥物動力學性質之影響 Effects of Paeoniae Radix on the Pharmacokinetics of Antiepileptic Agents
中文摘要
癲癇患者常併用許多不同的抗癲癇藥物治療，依吾人先前的研究報告顯示，除
了標準的治療藥物外，有達16%的癲癇病患會合併使用相關的傳統中藥，因此
抗癲癇藥與中藥的交互作用研究亟待評估。芍藥(Paeoniae Radix; PR)傳統用於鎮 靜、鎮痙，臨床常用於鎮靜安神的中藥方劑組成中亦多含有芍藥，且目前研究已 證實其活性代謝物確具抗痙攣活性，因此芍藥亦常用於癲癇患者的輔助治療。另 phenytoin, carbamazepine, valproic acid 均為臨床常用的抗癲癇藥物，其治療範圍 狹窄，且代謝途徑主要係經由體內酵素系統(如 CYP450, UDPGT)進行轉化，因 此已有不少抗癲癇藥物與其他藥物併用產生交互作用之臨床報告，然這些抗癲 癇藥物與傳統中藥併用可能有的交互作用研究目前仍闕如。
為探討中藥與抗癲癇藥物間可能潛在的交互作用問題，本研究將分別以芍藥與 phenytoin (PHT), carbamazepine (CBZ)及 valproic acid (VPA)合併使用，評估芍藥
對此些抗癲癇藥藥動學參數及蛋白結合之影響程度。其中phenytoin 及
carbamazepine 部份係以 SD 大鼠進行實驗，而 valproic acid 部份之試驗計劃業經 台北榮民總醫院藥事(藥品臨床試驗)委員會審查通過以健康受試者進行試驗。血
液檢品之定量分析，係分別利用HPLC 及螢光偏極化免疫分析(FPIA)進行濃度
測定。
依本研究結果，PHT 與芍藥水萃取物併用時，其 Tmax 明顯較單獨投予 PHT 時 為大，Vd/F 較單獨投予 PHT 時為小，至於其他藥動學參數
Cmax、AUC、CL/F、T1/2 及 MRT，兩組間無統計上差異。另 PHT 的蛋白結合率
在芍藥與PHT 併用下與單獨投予 PHT 時相較，亦無統計上之差異。而 CBZ 與芍
藥水萃取物併用時，其CBZ 之 Tmax 明顯較單獨投予 CBZ 時為小，此外，CBZ 單獨使用或與芍藥併用時，其AUC、Cmax、Vd/F、CL/F、T1/2 及 MRT 均無統計
學上差異。但芍藥與CBZ 併用下，其 CBZ 的蛋白結合率較單獨投予 CBZ 時為
低，有統計上差異。至於VPA 單獨使用或與芍藥併用時相較，其
Tmax、Cmax、AUC Vd/F、CL/F、T1/2 及 MRT 均無統計學上差異。此外，芍藥與 VPA 併用下，其 VPA 的蛋白結合率與單獨投予 VPA 時亦無統計上之差異。本論 文的相關研究結果，除探討芍藥與抗癲癇藥物間之交互作用及其臨床意義外，
並將進以提供臨床治療應用及療效安全性評估之參考。
英文摘要
Except for the standard antiepileptic drugs, traditional Chinese medicines (TCM) are used for the treatment of epilepsy in oriental countries. We previously reported that many patients (16.32 %) used or had used TCM for the treatment of epilepsy even
when scientific medicine has been provided. Therefore, the interactions between antiepileptic drugs and TCM represent a potential problem for the treatment of epilepsy. Interactions between TCM and antiepileptic drugs may increase or decrease the pharmacological or toxicological effects of either component, however, lack of report about the pharmacokinetic interactions between antiepileptic drugs and TCM.
Since Paeoniae Radix (PR) is one of the TCM used as an adjuvant agent in some epileptic patients and may be administered concomitantly with antiepileptic drugs in clinical situations, the present study was conducted to evaluate the influences of PR on the pharmacokinetics and protein binding of the widely prescribed antiepileptic drugs, phenytoin (PHT), carbamazepine (CBZ) and valproic acid (VPA).
A single dose of test drug alone or in combination with PR extract was administered, respectively. The serial blood samples were obtained and measured by high-
performance liquid-chromatography (HPLC). The free (unbound) plasma
concentrations were determined by fluorescence polarization immunoassay (FPIA).
The plasma concentrations were used to construct pharmacokinetic profiles by plotting drug concentration-time curves. All data were subsequently processed by the computer program WINNONLIN (SCI, Lexington).
In the study results, the mean maximum plasma concentration of PHT was attained at within 2 h after oral administration of PHT alone and 4-6 h after oral administration of PHT in combination with PR. The plasma level of PHT declined with a half-life of 5.38 and 4.03 h, respectively. No statistically significant differences were obtained in most of pharmacokinetic parameters (Cmax, AUC, T1/2, MRT and CL/F) and protein binding rates of PHT between the two treatments, however, the significant differences in Tmax and Vd/F between groups were noted.
In addition, the mean maximum plasma concentration of CBZ was attained at 1-4 h after oral administration of CBZ alone and within 2 h after oral administration of CBZ in combination with PR. The significant decrease in Tmax of CBZ was noted when CBZ was combined with PR. The plasma level of CBZ declined with a half-life of 8.60 and 7.69 h, respectively. There were no significant differences in Cmax, AUC, T1/2, MRT, CL/F and Vd/F of CBZ between the two groups. A significant decrease in protein binding rate was found while CBZ was co-administered with PR. Further studies are in progress to clarify the clinical significance and the mechanism
underlying the effects of PR on the protein binding of CBZ.
Finally, the mean maximum plasma concentration of VPA was attained at within 6 h after oral administration of VPA alone and 3-4 h after oral administration of VPA in combination with PR. The plasma level of VPA declined with a half-life of 11.71 and 11.91 h, respectively. No statistically significant difference was obtained in all
pharmacokinetic parameters (Tmax, Cmax, AUC, T1/2, MRT, CL/F and Vd/F) of
VPA between the two treatments. Also, there was no significant difference in the protein binding rates of VPA
The pharmacokinetic interaction between antiepileptic drugs and PR are revealed to anticipate the efficacy and to reduce the risk of antiepileptic drugs in clinical
applications.
