Determination of Pharmacokinetics of Chrysin and Its Conjugates in Wild-Type FVB and Bcrp1 Knockout Mice Using a Validated LC-MS/MS Method

Chrysin, a flavone found in many plants, is also available as a dietary supplement because of its reported anticancer activities. However, its bioavailability is very poor due to extensive phase II metabolism. The purpose of this study was to develop an UPLC-MS/MS method to simultaneously quantify chrysin and its phase II metabolites, and to determine its pharmacokinetics in FVB wild-type and Bcrp knockout (Bcrp1 −/−) mice. In addition, the role of BCRP in chrysin phase II disposition was further investigated in Caco-2 cells. The results showed that our sensitive and reproducible UPLC-MS/MS method was successfully applied to the pharmacokinetic study of chrysin in wild-type and Bcrp1 (−/−) FVB mice after oral administration (20 mg/kg). Although there was no significant change in systemic exposure of chrysin and its metabolites, it was found that the <i>T</i>_max for chrysin glucuronide was significantly shorter (<i>p</i> < 0.01) in Bcrp1-deficient mice. Furthermore, it was shown that inhibition of BCRP by Ko143 significantly reduced the efflux of chrysin sulfate in Caco-2 cells. In conclusion, BCRP had significant but less than expected impact on pharmacokinetics of chrysin and its conjugates, which were determined using a newly developed and validated LC-MS/MS method

Transport–Glucuronidation Classification System and PBPK Modeling: New Approach To Predict the Impact of Transporters on Disposition of Glucuronides

Glucuronide metabolites require the action of efflux transporters to exit cells due to their hydrophilic properties. In this study, we proposed a transport–glucuronidation classification system and developed a PBPK model to predict the impact of BCRP on systemic exposure of glucuronides. The clearance by UGTs in S9 fractions and the efflux clearance of glucuronides by BCRP in human UGT1A9-overexpressing HeLa cells were incorporated in the classification system and PBPK model. Based on simulations for glucuronide AUC for theoretical compounds in the classification system, it was indicated that BCRP was more important for compounds with greater efflux clearance of their glucuronides by BCRP regardless of differences in clearance by UGTs. Pharmacokinetic studies were performed in WT and Bcrp1 (−/−) mice for 8 compounds to verify our predictions. Among eight compounds, the glucuronide AUC of daidzein and genistein increased significantly in Bcrp1 (−/−) mice, while only slight increases in systemic exposure were observed for other glucuronides. The results from pharmacokinetic studies were in agreement with the predictions except for resveratrol, which was effluxed predominantly by transporters other than BCRP. Therefore, for glucuronides that were predominantly mediated by BCRP, this study provided a useful approach in predicting the impact of BCRP on its disposition and the potential DDIs involving BCRP

Role of Filler Shape and Connectivity on the Viscoelastic Behavior in Polymer Nanocomposites

We compare the rheological behavior of three classes of polymer nanocomposites (PNCs) to understand the role of particle shape and interactions on mechanical reinforcement. The first two correspond to favorably interacting composites formed by mixing poly­(2-vinylpyridine) with either fumed silica nanoparticles (NPs) or colloidal spherical silica NPs. We show that fumed silica NPs readily form a percolated network at low NP volume fractions. We deduce that the NPs act as network junctions with the effectively irreversibly bound polymer chains serving as the connecting bridges. By comparing with colloidal spherical silica, which has a significantly higher percolation threshold, we conclude that the fractal shape of the fumed silica is responsible for its unusually low percolation threshold. The third system corresponds to polystyrene grafted colloidal silica nanoparticles (PGNPs) in a polystyrene matrix. These PNCs have an even lower percolation threshold probably because the grafted chains increase the effective volume fraction of the NPs. When we take these different thickness of the polymer layers in the two cases into account (i.e., grafted layer vs adsorbed layer thickness), the percolation threshold for the fumed and the grafted system occurs at similar effective loadings, but the NP network with fumed silica has a higher low-frequency plateau modulus than that formed with the PGNPs. These findings can be reconciled by the fact that the fumed silica NPs are composed of fused entities, thus ensuring that they have a higher modulus than the PGNPs where the modulus is largely attributed to interactions between the grafts. Our results systematically stress the important role of the nanofiller shape and connectivity on the mechanical reinforcement of PNCs