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Prediction of Drug–Drug Interaction between Tacrolimus and Principal Ingredients of Wuzhi Capsule in Chinese Healthy Volunteers Using Physiologically‐Based Pharmacokinetic Modelling
Author(s) -
Zhang Hongyan,
Bu Fengjiao,
Li Lei,
Jiao Zheng,
Ma Guo,
Cai Weimin,
Zhuang Xiaomei,
Lin HaiShu,
Shin JaeGook,
Xiang Xiaoqiang
Publication year - 2018
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12914
Subject(s) - physiologically based pharmacokinetic modelling , tacrolimus , pharmacokinetics , pharmacology , cyp3a4 , chemistry , drug , drug interaction , capsule , drug drug interaction , metabolism , medicine , biochemistry , biology , cytochrome p450 , transplantation , botany
Schisantherin A and schisandrin A, the most abundant active ingredients of Wuzhi capsule, are known to inhibit tacrolimus metabolism by inhibiting CYP 3A4/5. 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 CYP 3A4/5 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.