Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China.
Expert Opin Drug Metab Toxicol. 2021 Jan;17(1):121-134. doi: 10.1080/17425255.2021.1837111. Epub 2020 Nov 6.
Epigallocatechin-3-gallate (EGCG) is the most biologically active catechin of green tea. Tacrolimus (TAC) and cyclosporine A (CsA) are immunosuppressive agents commonly used in clinical organ transplantation. The present study investigated the effect of EGCG on the pharmacokinetics of TAC and CsA in rats and its underlying mechanisms.
Either TAC or CsA was administered to rats intravenously or orally with or without concomitant EGCG. Polymerase Chain Reaction and Western Blot were used to determine the effect of EGCG on drug-metabolizing enzymes (DMEs), drug transporters (DTs) and nuclear receptors (NRs).
The C and AUC of TAC were reduced, and V/F and CL/F of TAC were enhanced after co-administration of EGCG. EGCG increased the Cmax, AUC of CsA at 3 ~ 30 mg∙kg-1 dosages, while decreased those parameters at the dosage of 100 mg∙kg-1. EGCG inhibited the mRNA and protein expressions of DMEs and DTs, such as CYP3A1, A2, UGT1A1, Mdr1 and Mrp2, but upregulated the expressions of Car, Pxr and Fxr.
These results revealed consumption of high dose EGCG may cause a significant alteration in pharmacokinetics of TAC and distribution/elimination profiles of CsA through the regulation of DMEs, DTs and NRs.
表没食子儿茶素没食子酸酯（EGCG）是绿茶中最具生物活性的儿茶素。他克莫司（TAC）和环孢素 A（CsA）是临床器官移植中常用的免疫抑制剂。本研究旨在探讨 EGCG 对大鼠 TAC 和 CsA 药代动力学的影响及其机制。
TAC 或 CsA 分别经静脉或口服给予大鼠，同时或不合并 EGCG。聚合酶链反应和 Western Blot 用于确定 EGCG 对药物代谢酶（DMEs）、药物转运体（DTs）和核受体（NRs）的影响。
与单独使用 TAC 相比，合并 EGCG 后 TAC 的 C 和 AUC 降低，V/F 和 CL/F 增加。EGCG 增加了 3 至 30mg·kg-1 剂量的 CsA 的 Cmax 和 AUC，但在 100mg·kg-1 剂量时降低了这些参数。EGCG 抑制了 DMEs 和 DTs 的 mRNA 和蛋白表达，如 CYP3A1、A2、UGT1A1、Mdr1 和 Mrp2，但上调了 Car、Pxr 和 Fxr 的表达。
这些结果表明，高剂量 EGCG 的摄入可能通过调节 DMEs、DTs 和 NRs 导致 TAC 的药代动力学和 CsA 的分布/消除特征发生显著改变。
