Guangdong Food and Drug Vocational College, Guangzhou, PR China.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
J Ethnopharmacol. 2020 Dec 5;263:113233. doi: 10.1016/j.jep.2020.113233. Epub 2020 Aug 5.
Tacrolimus is a well-known potent but expensive immunosuppressant. We previously clarified the herb-drug interaction between tacrolimus and Wuzhi tablet (WZ), a prescribed drug of ethanol extract of Schisandra sphenanthera, and showed the ideal effect of WZ on maintaining therapeutic level of tacrolimus and reducing the total drug expense. However, WZ possesses a biphasic effect on regulating CYP3A (the major metabolizing enzyme of tacrolimus), which could induce the mRNA and protein expression after long-term treatment while transiently inhibit the activity of CYP3A. In clinic, clinicians are confused about the relationship between the blood concentration of tacrolimus and the dose and the duration of pretreatment of WZ. Therefore, the effects of the pretreatment time and the dose of WZ on the pharmacokinetics of tacrolimus is urgently needed to be clarified to better combine the use of WZ and tacrolimus in clinic.
This study aimed to investigate the effects of the pretreatment time and the dose of WZ on the pharmacokinetics of tacrolimus in rats.
After pretreated rats with WZ for 0, 0.5, 2, 6, 12 or 24 h, the area under the curve (AUC) of tacrolimus was 2.27 ± 0.59, 1.87 ± 1.14, 2.86 ± 0.64, 1.62 ± 0.70, 1.54 ± 1.06 and 1.12 ± 0.69-fold of that of the tacrolimus alone group, respectively. The ratio of AUC of tacrolimus to that of the co-administration group with 0, 62.5, 125, 250, 500 or 750 mg/kg of WZ was 1.00: 1.07: 1.44: 2.60: 2.32: 2.42, respectively. These findings suggested that WZ increased tacrolimus AUC in a pretreatment time- and dose-dependent manner. In line with the in vivo findings, WZ extract inhibited CYP3A activity in a pre-treatment time- and concentration-dependent manner in human liver microsomes. In conclusion, the pharmacokinetics of tacrolimus was significantly affected by the pretreatment time and the dose of WZ. Oral pretreatment with WZ for 0-2 h or co-dosing of 250 mg/kg of WZ most significantly increased the blood concentration of tacrolimus. These findings would be helpful for guiding the reasonable use of WZ and tacrolimus in clinic.
他克莫司是一种众所周知的强效但昂贵的免疫抑制剂。我们之前已经阐明了他克莫司与五指片（WZ）之间的草药-药物相互作用，WZ 是五味子的乙醇提取物的处方药，并且显示了 WZ 对维持他克莫司治疗水平和降低总药物费用的理想效果。然而，WZ 对 CYP3A（他克莫司的主要代谢酶）的调节具有双相作用，长期治疗后会诱导 CYP3A 的 mRNA 和蛋白表达，而短期抑制 CYP3A 的活性。在临床上，临床医生对他克莫司的血药浓度与 WZ 的剂量和预处理时间之间的关系感到困惑。因此，迫切需要阐明 WZ 的预处理时间和剂量对他克莫司药代动力学的影响，以便更好地将 WZ 和他克莫司联合用于临床。
本研究旨在探讨 WZ 的预处理时间和剂量对大鼠他克莫司药代动力学的影响。
WZ 预处理大鼠 0、0.5、2、6、12 或 24 小时后，他克莫司的 AUC 分别为他克莫司单用时的 2.27±0.59、1.87±1.14、2.86±0.64、1.62±0.70、1.54±1.06 和 1.12±0.69 倍。与 WZ 0、62.5、125、250、500 或 750mg/kg 联合给药组的 AUC 比值分别为 1.00:1.07:1.44:2.60:2.32:2.42。这些发现表明 WZ 以预处理时间和剂量依赖的方式增加他克莫司的 AUC。与体内发现一致，WZ 提取物在人肝微粒体中以预处理时间和浓度依赖的方式抑制 CYP3A 活性。总之，WZ 的预处理时间和剂量显著影响他克莫司的药代动力学。WZ 口服预处理 0-2 小时或联合给予 250mg/kg 的 WZ 可显著增加他克莫司的血药浓度。这些发现将有助于指导 WZ 和他克莫司在临床上的合理应用。
