Prediction of Drug-Drug Interaction between Tacrolimus and Principal Ingredients of Wuzhi Capsule in Chinese Healthy Volunteers Using Physiologically-Based Pharmacokinetic Modelling
Prediction of Drug-Drug Interaction between Tacrolimus and Principal Ingredients of Wuzhi Capsule in Chinese Healthy Volunteers Using Physiologically-Based Pharmacokinetic Modelling
复制标题
使用基于生理学的药代动力学模型预测中国健康志愿者中他克莫司和五脂胶囊主要成分之间的药物相互作用。
DOI：
10.1111/bcpt.12914
复制
发表时间：
2018-03-01
影响因子：
3.1
通讯作者：
Xiang, Xiaoqiang
中科院分区：
文献类型：
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作者：
Zhang, Hongyan;Bu, Fengjiao;Xiang, Xiaoqiang
已知五酯胶囊中含量最丰富的活性成分芍药苷A和五味子醇甲通过抑制CYP 3A 4/5抑制他克莫司代谢。采用生理药代动力学（PBPK）模型预测五味子甲素和五味子醇甲对五酯胶囊与他克莫司间药物相互作用（DDI）的贡献。首先，探讨了五味子甲素和五味子乙素对CYP 3A 4/5的抑制机制。建立了五味子甲素、五味子甲素和他克莫司的PBPK模型。最后，评价了他克莫司与五味子甲素或五味子甲素合用后的药代动力学。单次和多次给予五味子酯甲后，他克莫司的血药曲线下面积（AUC）分别增加了1.77倍和2.61倍。五味子甲素对他克莫司代谢的抑制作用较小。此外，它表明，基于机制的抑制（MBI）在DDI中发挥的作用比长期给药后的可逆抑制更重要，而单次给药后的可逆抑制与MBI相当。总之，我们利用PBPK模型来量化五味子甲素和五味子甲素对他克莫司和五酯胶囊间DDI的贡献。这可能为合理使用该药物组合提供更多的见解。
Schisantherin A and schisandrin A, the most abundant active ingredients of Wuzhi capsule, are known to inhibit tacrolimus metabolism by inhibiting CYP3A4/5. We aimed to predict the contribution of schisantherin A and schisandrin A to drug-drug interaction (DDI) between Wuzhi capsule and tacrolimus using physiologically-based pharmacokinetic (PBPK) modelling. Firstly, the inhibition mechanism of schisantherin A and schisandrin A on CYP3A4/5 was investigated. Thereafter, PBPK models of schisantherin A, schisandrin A and tacrolimus were established. Finally, tacrolimus pharmacokinetics were evaluated after the combined use with schisantherin A or schisandrin A. The blood area under the curve (AUC) of tacrolimus increased 1.77- and 2.61-fold after a single dose and multiple doses of schisantherin A, respectively. Meanwhile, schisandrin A inhibited tacrolimus metabolism to a smaller extent. Also, it showed that mechanism-based inhibition (MBI) played a more important role in DDI than reversible inhibition after long-term administration, while reversible inhibition was comparable to MBI after single-dose administration. In conclusion, we utilized PBPK modelling to quantify the contribution of schisantherin A and schisandrin A to DDI between tacrolimus and Wuzhi capsule. This may provide more insights for the rational use of this drug combination.