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.
Highlights
The pharmacokinetic drug–drug interaction (DDI) is usually caused by the interference of a perpetrator drug on the metabolizing enzymes or drug transporters of a victim drug.Genetic polymorphisms that alter these enzymes or transporters thereby can affect the magnitude of a DDI
2C), suggesting little tration increased in the incubation with CYP3A5*3/3 human liver microsomes (HLMs) (Figure 2C), suggesting littlereversible inhibition on CYP3A4 by schisandrin A (SIA)
The results indicated that schisantherin A (STA) showed a potent time-dependent inhibition (TDI) profile on CYP3A4 (Figure 3A,B) while this was not observed on CYP3A5 (Figure 3C)
Summary
The pharmacokinetic drug–drug interaction (DDI) is usually caused by the interference of a perpetrator drug on the metabolizing enzymes or drug transporters of a victim drug. Genetic polymorphisms that alter these enzymes or transporters thereby can affect the magnitude of a DDI. Tacrolimus metabolism inhibition is significantly greater in renal transplant recipients lacking CYP3A5*1 allele with no functional enzyme activity [1]. As a first-line immunosuppressive agent for organ transplant patients, tacrolimus is mainly metabolized by CYP3A4 and CYP3A5 [1,2]. The polymorphism of CYP3A5 accounts for 40–50% of the variability in tacrolimus dose requirement [4]. The primary determinant of this pharmacogenetic effect is a single-nucleotide polymorphism (SNP) in determinant this pharmacogenetic is a single-nucleotide (SNP)
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