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Valsartan is widely used for the treatment of moderate hypertension. However, previous studies have found that efficacy of the valsartan depends on the dose and intake. Cytochrome P450 (CYP) 2C9 metabolizes ∼15% of the clinical drugs. Genetic polymorphisms of CYP2C9 markedly affect the safety and effectiveness of many drugs, which might lead to adverse reactions and therapeutic failure. Twenty-four novel CYP2C9 variants (*36–*60) had been previously discovered via gene sequencing in the Han population. Our study aims to evaluate the impact of 38 CYP2C9 variants from the Chinese population on valsartan metabolism compared with CYP2C9 *1 in vitro. Wild-type CYP2C9 *1 and other CYP2C9 variants were expressed in Spodoptera frugiperda 21 insect cells. Incubations were performed at 37 °C with 20–2000 μM substrate for 30 min. The metabolite 4-OH valsartan was determined via UPLC-MS/MS. Among the 38 CYP2C9 variants, the enzymatic activities of most variants were significantly altered compared with the wild-type. Three variants (CYP2C9 *27, *40 and *49) exhibited increased intrinsic clearance values (134–153% relative clearance). However, 12 variants (CYP *8, *13, *16, *19, *33, *36, *42, *43, *45, *52, *54, *58) caused >90% decreases in the relative clearance of valsartan compared to CYP2C9 *1. Our research provides systematic data for evaluating the effects of CYP2C9 variants on valsartan metabolism in the Chinese population. These results will expand our understanding of the impact of CYP2C9 genetic polymorphisms on valsartan metabolism and will contribute to precision medicine. • We identified 24 novel CYP2C9 alleles in the Han Chinese population in the previous study. • We evaluate the catalytic activities of 38 CYP2C9 alleles variants toward valsartan in vitro. • There are 35 variants showed decreased catalytic activity toward valsartan. [ABSTRACT FROM AUTHOR]

Influence of particle angularity on the suffusion in gap-graded granular soils remains unclear up to now. In this study, systematical numerical simulations that consider the particle shape as quasi-spherical polyhedra in different angularity are performed with the coupled discrete element method (DEM) and the computational fluid dynamics (CFD) approach. The suffusion of six gap-graded soil samples with 25% fines content is examined by imposing an upward seepage flow. Conventional triaxial tests are also conducted on the pre-eroded and post-eroded specimens to study the coupling influence of angularity and suffusion on the mechanical characteristics of granular soils. Fines loss, vertical displacement, soil strength, volume flow rate, microstructural analyses of force networks, the cumulative percentage of contact force, and the anisotropy of contact are investigated. Results turn out that the angularity intensifies the internal erosion resistance as the fines loss decreases significantly with the increasing angularity. The soil peak strength and friction angle are approximately linearly correlated with angularity. Erosion-induced particle redistribution reduces the degree of anisotropy of contact normal and contact normal force. This study may improve our understanding of the effect of particle angularity on suffusion with both microscopic and macroscopic evidence. [ABSTRACT FROM AUTHOR]

This paper establishes a semi-analytical lower-bound dynamic shakedown method to investigate the shakedown of the pavement on saturated subgrade based on dynamic Biot's consolidation theory, considering a rolling-sliding contact between vehicle tire and pavement. This analysis has demonstrated that properties of the saturated subgrade generally have negative effects on the shakedown limit of the pavement system under high-speed traffic loadings. In general, the classical single-phased shakedown theorem overestimates the shakedown limit of the pavement on the soft ground of low permeability, particularly under high-speed traffic loadings. The shakedown limit of the pavement on a saturated subgrade gradually reduces with decreasing permeability of the subgrade. The sliding-induced friction significantly affects the shakedown limit and the location of critical shakedown failure. The permeability of the saturated subgrade has considerable effects on the shakedown limit for the case of low tire-pavement friction. The shakedown limit of the pavement on a saturated subgrade and a single-phased subgrade shows a considerable difference at the optimum modulus ratio, at which the critical shakedown failure tends to shift from the saturated subgrade to the pavement layer. The proposed method will be more desirable to evaluate the performance of the pavement in the saturated soft ground. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the effect of flavonoids on midostaurin disposition considering co-administration and metabolic enzyme gene polymorphism. Enzymatic incubation assays were performed in vitro , while in vivo experiments were conducted in Sprague–Dawley rats. The analytes were determined via UPLC-MS/MS. We found that myricetin was the most potent among the investigated 10 flavonoids in suppressing the metabolism of midostaurin, with an IC 50 at a low μM level. After co-administration of midostaurin and myricetin, the plasma concentration of midostaurin's primary metabolite CGP62221 was reduced corresponding to myricetin exposure. Furthermore, CYP3A4 homologous rat protein CYP3A2 was reduced significantly in the co-administration group. Thereafter, the kinetic parameters of 23 recombinant human CYP3A4 variants were determined using midostaurin. The relative intrinsic clearance varied from 269.63% in CYP3A4.29–8.95% in CYP3A4.17. In addition, the inhibitory potency of myricetin was substantially different for CYP3A4.29 and CYP3A4.17 compared with wild type, with IC 50 values of 9.85 ± 0.27 μM and 90.99 ± 16.13 μM, respectively. Collectively, our data demonstrated that flavonoids, particularly myricetin, can inhibit the metabolism of midostaurin. Additionally, CYP3A4 genetic polymorphism may contribute to stratification of midostaurin blood exposure. [Display omitted] • Flavonoids, particular myricetin, can inhibit the metabolism of midostaurin. • Myricetin inhibits the metabolism of midostaurin by uncompetitive mechanism in human liver microsomes. • CYP3A4 gene polymorphism results in differential inhibitory efficacy of myricetin in midostaurin metabolism. [ABSTRACT FROM AUTHOR]