Investigation of the Impact of <i>CYP3A5</i> Polymorphism on Drug–Drug Interaction between Tacrolimus and Schisantherin A/Schisandrin A Based on Physiologically-Based Pharmacokinetic Modeling

Abstract

Wuzhi capsule (WZC) is commonly prescribed with tacrolimus in China to ease drug-induced hepatotoxicity. Two abundant active ingredients, schisantherin A (STA) and schisandrin A (SIA) are known to inhibit CYP3A enzymes and increase tacrolimus’s exposure. Our previous study has quantitatively demonstrated the contribution of STA and SIA to tacrolimus pharmacokinetics based on physiologically-based pharmacokinetic (PBPK) modeling. In the current work, we performed reversible inhibition (RI) and time-dependent inhibition (TDI) assays with CYP3A5 genotyped human liver microsomes (HLMs), and further integrated the acquired parameters into the PBPK model to predict the drug–drug interaction (DDI) in patients with different CYP3A5 alleles. The results indicated STA was a time-dependent and reversible inhibitor of CYP3A4 while only a reversible inhibitor of CYP3A5; SIA inhibited CYP3A4 and 3A5 in a time-dependent manner but also reversibly inhibited CYP3A5. The predicted fold-increases of tacrolimus exposure were 2.70 and 2.41, respectively, after the multidose simulations of STA. SIA also increased tacrolimus’s exposure but to a smaller extent compared to STA. An optimized physiologically-based pharmacokinetic (PBPK) model integrated with CYP3A5 polymorphism was successfully established, providing more insights regarding the long-term DDI between tacrolimus and Wuzhi capsules in patients with different CYP3A5 genotypes.

Keywords

• physiologically-based pharmacokinetic (PBPK)
• Wuzhi capsule (WZC)
• tacrolimus
• <i>CYP3A5</i> polymorphism
• drug–drug interaction (DDI)
• schisantherin A (STA)