Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Guangdong Pharmaceutical University, Guangdong Academy of Medical Sciences, Guangzhou, China.
Department of Pediatrics, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Academy of Medical Sciences, Guangzhou, China.
Pharmazie. 2020 Nov 1;75(11):559-564. doi: 10.1691/ph.2020.0635.
The co-administration of voriconazole (VCZ) and Wuzhi tablet (WZ) is frequently prescribed for solid organ transplantation patients in China. However, the pharmacokinetic interactions between VCZ and WZ as well as its bioactive constituents, such as schisandrin A and schisandrol B, remain unknown. Therefore, the effects of WZ and the two lignans on the metabolism of VCZ and the potential role of cytochromeP450 (CYP450), especially cytochrome P450 2C19 (CYP2C19), were investigated. The results showed that WZ extensively inhibited the activities of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. Noteworthy, 2.5 mg/mL WZ almost completely inhibited the activity of 2C19, and the inhibition ratio reached 78.6±3% and 63.5±4.6% for schisandrin A and schisandrol B at concentrations 100 μM, respectively. In addition, rats were treated with a single or consecutive 14 day oral dose of WZ (250 mg/kg), schisandrol B (10 mg/kg) and schisandrin A (10 mg/ kg). In rats treated with WZ, the AUC value for intravenous VCZ dosing was increased by 80.2% (single dose, < 0.05) and 66.4% (dosage for 14 day, < 0.05) and the C was increased by 10.5% ( < 0.05) and (20.6%, < 0.05), respectively, much greater than that when VCZ (28 mg/kg) was given alone. Unexpectedly, the AUC and C values after schisandrol B and schisandrin A treatment were significantly increased. However, the mRNA expression of liver CYP2C19 and the protein expression of liver CYP2C19 were surprisingly increased after treatment with WZ, schisandrol B and schisandrin A in rats. Therefore, attention should be paid to when WZ and VCZ are administered concomitantly, as dosage adjustment might become necessary. Further clinical study is warranted to validate the interaction between WZ and VCZ.
在中国，伏立康唑（VCZ）和五味子片（WZ）联合给药常用于实体器官移植患者。然而，VCZ 与 WZ 及其生物活性成分（如五味子甲素和五味子醇 B）之间的药代动力学相互作用尚不清楚。因此，研究了 WZ 及两种木脂素对 VCZ 代谢的影响，以及细胞色素 P450（CYP450），特别是细胞色素 P450 2C19（CYP2C19）的潜在作用。结果表明，WZ 广泛抑制 CYP1A2、2A6、2B6、2C8、2C9、2C19、2D6、2E1 和 3A4 的活性。值得注意的是，2.5mg/mL 的 WZ 几乎完全抑制了 2C19 的活性，五味子甲素和五味子醇 B 在浓度为 100μM 时对 2C19 的抑制率分别达到 78.6±3%和 63.5±4.6%。此外，大鼠分别给予单次或连续 14 天口服 WZ（250mg/kg）、五味子醇 B（10mg/kg）和五味子甲素（10mg/kg）。在给予 WZ 的大鼠中，静脉注射 VCZ 给药后的 AUC 值增加了 80.2%（单次剂量，<0.05）和 66.4%（14 天剂量，<0.05），C 增加了 10.5%（<0.05）和 20.6%（<0.05），明显大于 VCZ（28mg/kg）单独给药时的 AUC 值。出乎意料的是，五味子醇 B 和五味子甲素治疗后的 AUC 和 C 值显著增加。然而，在大鼠给予 WZ、五味子醇 B 和五味子甲素后，肝 CYP2C19 的 mRNA 表达和肝 CYP2C19 的蛋白表达均显著增加。因此，当同时给予 WZ 和 VCZ 时应注意，可能需要调整剂量。需要进一步的临床研究来验证 WZ 和 VCZ 之间的相互作用。
