Zhaoyu Wang,Qingxia Ji,Tingting Wang,Weiliang Hua,Yanhong Bi,Yongzhou Chi,Rongling Yang
Schisantherin A (SCA) has recently attracted increasing attention because of its promising biological profile. However, poor aqueous solubility and bioavailability have limited the efficacy of SCA in pharmaceutical applications. In this study, novel complex CaCO 3 -based biomineralized microparticles that demonstrate significant potential as carriers for loading and delivering SCA were constructed for the first time by employing gum arabic as the stable template and polydopamine as the functional coating agent. The results show that these composite microparticles have a high SCA loading rate of 15.6 ± 0.4 % and a pH-responsive drug release characteristic under simulated in vitro conditions. Further investigation revealed that the encapsulated forms of SCA exhibit significantly enhanced synergistic antioxidant activity and antibacterial efficacy against Staphylococcus aureus compared to the carrier-free SCA. Furthermore, a 4′,6-diamidino-2-phenylindole (DAPI) staining experiment and a rhodamine 123 (Rh123) fluorescence staining test of lipopolysaccharide (PSL) induced BV-2 microglial cells demonstrated that the encapsulated form of SCA exhibits considerable efficacy in inducing changes in the morphology and structure of cells. With these findings, this study provides a new type of CaCO 3 -mediated particle carrier that is useful for targeted and controlled release applications.
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 withCYP3A5genotyped human liver microsomes (HLMs), and further integrated the acquired parameters into the PBPK model to predict the drug–drug interaction (DDI) in patients with differentCYP3A5alleles. 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 withCYP3A5polymorphism was successfully established, providing more insights regarding the long-term DDI between tacrolimus and Wuzhi capsules in patients with differentCYP3A5genotypes.
Deoxyschizandrin and schisantherin A are major bioactive lignans isolated from Fructus schisandrae which has been widely used as a tonic in traditional Chinese medicine for many years. Inhibition of UDP-glucuronosyltransferases (UGTs) by herbal components might be an important reason for clinical herb–drug interaction. The aim of the present study is to investigate the inhibitory effect of deoxyschizandrin and schisantherin A on major UGT isoforms. Recombinant UGT isoforms were used as enzyme source, and a nonspecific substrate 4-methylumbelliferone (4-MU) was utilized as substrate. The results showed that 100 μM of deoxyschizandrin and schisantherin A exhibited strong inhibition on UGT1A3, and negligible inhibition on other tested UGT isoforms. Furthermore, deoxyschizandrin and schisantherin A were demonstrated to inhibit UGT1A3 in a concentration-dependent manner, with IC 50 value of 10.8 ± 0.4 μM and 12.5 ± 0.5 μM, respectively. Dixon and Lineweaver–Burk plots showed that inhibition of UGT1A3 by deoxyschizandrin was best fit to competitive inhibition type, and inhibition kinetic parameter (K i ) was calculated to be 0.48 μM. Inhibition of UGT1A3 by schisantherin A gave the best fit for types of noncompetitive inhibition, and the results showed K i to be 11.3 μM. All these experimental data suggested that herb–drug interaction might occur when deoxyschizandrin or schisantherin A containing herbs were co-administered with drugs which mainly undergo UGT1A3-mediated metabolism. However, given that many in vivo factors could influence the in vitro – in vivo extrapolation (IVIVE), these in vitro inhibitory parameters should be considered with caution.
危险品化学品经营许可证（带存储）