Prediction of Drug–Drug Interaction between Tacrolimus and Principal Ingredients of Wuzhi Capsule in Chinese Healthy Volunteers Using Physiologically-Based Pharmacokinetic Modelling

Abstract

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.