Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China.
Drug Metab Dispos. 2013 Jul;41(7):1398-403. doi: 10.1124/dmd.112.050302. Epub 2013 Apr 29.
Wuzhi capsule (WZC) is a preparation of an ethanol herbal extract of Schisandra sphenanthera (Nan-Wuweizi), with its main active ingredients that include schisandrin, schizandrol B, schisantherin A, schisanhenol, and deoxyschizandrin. WZC and tacrolimus are often coadministered for the treatment of drug-induced hepatitis in organ transplant recipients in China. Recently, it was reported that WZC could significantly increase the blood concentration of tacrolimus. The purpose of this study was to investigate whether and how WZC affects the pharmacokinetics of tacrolimus in rats. Liquid chromatography-tandem mass spectrometry method was used to determine the plasma concentration of tacrolimus. The results showed that WZC increased the mean plasma concentration of tacrolimus. Compared with administration of tacrolimus alone [maximum plasma concentration (C(max)), 18.87 ± 10.29 ng/ml; area under the plasma concentration-time curve from time zero to last sampling time (AUC(0→t)), 40.98 ± 37.07 ng h/ml], a single intragastric administered dose of WZC increased the pharmacokinetic parameters of tacrolimus (C(max), 59.42 ± 30.32 ng/ml; AUC(0→t), 239.71 ± 28.86 ng h/ml) by 5-fold in rat plasma. After pretreatment with WZC for 12 days, there were still significant increases in AUC(0→t) (from 40.98 ± 37.07 to 89.21 ± 26.39 ng h/ml; P < 0.05) and C(max) (from 18.87 ± 10.29 to 43.16 ± 10.61 ng/ml; P < 0.05) of tacrolimus, compared with oral of tacrolimus alone, suggesting that WZC increased the exposure of tacrolimus by one or more mechanisms. The increase in tacrolimus C(max) by WZC was dose-dependent. The effect of WZC on tacrolimus AUC(0→t) also increased with dose, with a maximal effect observed at 450 mg/kg (825.34 ng h/ml). No further increases in tacrolimus AUC(0→t) were observed at WZC dose above 450 mg/kg. It is suggested that, because of the effect of WZC on the pharmacokinetics of tacrolimus, the herb-drug interaction between WZC and tacrolimus should be taken into consideration in clinical practice.
五酯胶囊（WZC）是五味子的乙醇提取物制剂，其主要活性成分包括五味子甲素、五味子醇 B、五味子酯 A、五味子醇乙和去氧五味子素。在中国，WZC 常与他克莫司联合用于治疗器官移植受者的药物性肝炎。最近有报道称，WZC 可显著增加他克莫司的血药浓度。本研究旨在探讨 WZC 是否及如何影响他克莫司在大鼠体内的药代动力学。采用液相色谱-串联质谱法测定他克莫司的血浆浓度。结果表明，WZC 增加了他克莫司的平均血浆浓度。与单独给予他克莫司相比[最大血浆浓度（C（max）），18.87±10.29ng/ml；从零时到最后采样时间的血浆浓度-时间曲线下面积（AUC（0→t）），40.98±37.07ng·h/ml]，大鼠单次灌胃给予 WZC 可使他克莫司的药代动力学参数（C（max），59.42±30.32ng/ml；AUC（0→t），239.71±28.86ng·h/ml）增加 5 倍。WZC 预处理 12 天后，他克莫司的 AUC（0→t）[从 40.98±37.07ng·h/ml 增加至 89.21±26.39ng·h/ml；P<0.05]和 C（max）[从 18.87±10.29ng/ml 增加至 43.16±10.61ng/ml；P<0.05]仍显著增加，表明 WZC 通过一种或多种机制增加了他克莫司的暴露量。WZC 增加他克莫司 C（max）呈剂量依赖性。WZC 对他克莫司 AUC（0→t）的影响也随剂量增加而增加，在 450mg/kg 时达到最大效应（825.34ng·h/ml）。WZC 剂量超过 450mg/kg 时，他克莫司 AUC（0→t）未见进一步增加。提示由于 WZC 对他克莫司药代动力学的影响，在临床实践中应考虑 WZC 与他克莫司之间的草药-药物相互作用。
