近年替代療法風行，植物藥是最常用的。因此，當植物藥與西藥併服時，對於西藥動力學、療效與安全之影響是值得關注的問題。大黃、虎杖為重要的蓼科中藥，富含蒽醌、二苯乙烯等多酚。許多多酚已知為P-glycoprotein (P-gp) 或cytochrome P450 (CYPs) 之調控劑，且多酚吸收後，血中存在的分子主要為 glucuronides 及 sulfates，則成為 multidrug resistance protein 2 (MRP2) 之可能受質。
Carbamazepine (CBZ) 與 phenytoin (PHT) 為臨床上治療癲癇之第一線藥物，但其治療視窗狹窄。CBZ 為 CYP 3A 所代謝，形成活性代謝物carbamazepine-10,11-epoxide (CBZE)。PHT已知為P-gp、MRP 2之受質。本研究以大鼠為模型，探討併服單劑與多劑虎杖、大黃對 CBZ 及 PHT 動力學之影響，並利用體外模型探討其機轉。
研究結果顯示，(1)：併服單劑與多劑虎杖時，CBZ 及 CBZE之血藥面積皆顯著增加，腦、肝、腎等組織中濃度亦顯著增加。主要機轉為，虎杖抑制了 CYP 3A4 之活性，且抑制了 MRP 2 對 CBZE之外排。(2)：併服單劑大黃時，CBZ 及 CBZE 之血藥面積，腦、肝、腎等組織中濃度皆顯著增加。主要機轉為大黃抑制 CYP 3A4 之活性，並抑制 MRP 2 對 CBZE 之外排。然而，服用多劑大黃後，CBZ 之早期暴露顯著降低，而 CBZ 與 CBZE 之後期暴露量卻皆顯著增加。主要因為多劑量大黃誘導了 CYP 3A之mRNA，並抑制 MRP 2 對 CBZE 之外排。(3)：併服單劑量虎杖時，PHT 之血藥面積顯著降低，主要機轉為虎杖提高了 P-gp 之活性。然而，服用多劑量虎杖後，PHT 之血藥面積反而顯著增加，主要機轉為其抑制了 MRP 2 對PHT 之外排。(4)：併服單劑、多劑量大黃時，PHT 之最高血藥濃度與血藥面積皆顯著降低，主要機轉為大黃提升了 P-gp 之活性。
綜言之，大黃、虎杖藉由調控 CYP 3A、P-gp 及 MRP 2 等蛋白，造成 CBZ、PHT 藥物動力學之顯著改變，對其臨床療效與安全之影響究竟是風險、還是利基，值得進一步進行轉譯醫學研究加以評估。
The use of alternative medicine has increased worldwide in recent decades. Botanical products were the most popularly used. Therefore, the effects of botanics on the pharmacokinetics and pharmacodynamics of cretical medicines warrant investigations. Polygonum cuspidatum (PC) and Rheum palmatum (RP), important herbs in Chinese medicine, contain rich polyphenols such as anthraquinones and stilbenes. Polyphenols have been reported as modulators of P-glycoprotein (P-gp) and cytochrome P450 (CYPs). Pharmacokinetic studies have found that polyphenols were extensively metabolized into their glucuronides and sulfates, which were putative substrates of multidrug resistance proteins (MRPs).
Carbamazepine (CBZ) and phenytoin (PHT) are antiepileptic with narrow therapeutic window. CBZ is metabolized by CYP 3A to form carbamazepine-10,11-epoxide (CBZE), an active metabolite. PHT is a substrate of P-gp and MRP 2. This study investigated the acute and chronic effects of the PC and RP on the pharmacokinetics of CBZ and PHT in rats and the underlying mechanisms.
The results are (1): single dose and multiple doses of PC significantly increased the AUC and the concentrations of CBZ and CBZE in brain, liver and kidney. Mechanism studies suggested that PC inhibited the activities of CYP 3A and MRP 2. (2): Sigle dose of RP significantly increased the AUC and the concentrations of CBZ and CBZE 2 in brain, liver and kidney. Mechanism studies suggested that RP inhibited the activities of CYP 3A and MRP 2. However, multiple doses of RP significantly decreased the early exposure of CBZ, whereas the late exposure of CBZ and CBZE were significantly enhanced. In vitro studies indicated RP induced the expression of CYP 3A mRNA, whereas the activity of MRP 2 was inhibited. (3): Single dose of PC significantly decreased the AUC of PHT. In vitro study indicated PC induces the activity of P-gp. However, multiple doses of PC significantly increased the AUC of PHT. In vitro study suggested that PC inhibited the activity of MRP 2. (4): Single dose and multiple doses of RP significantly decreased the AUC of PHT. In vitro study indicated that RP induces the activity of P-gp.
In conclusion, coadministration of PC and RP significantly altered the pharmacokinteics of CBZ and PHT via modulation on CYP 3A, P-gp and MRP 2. Whether the combined therapy is a risk or benefit warrants more translation studies.
