Texture and Magnetic Property of Fe-6.5 wt % Si Steel Strip with Cu-Rich Particles Modification.

Based on the ordered phase effectively suppressed by rapid solidification technology, the grain refinement concept using Cu is incorporated into the soft magnetic materials. Cu dosage not only could refine the grain size with an average grain size of 8.7 µm but also improve the continuity and consistency of Fe-6.5 wt % Si steel strip. It mainly attributes to the Cu-rich particles precipitating at the grain boundary, nailing the grain boundaries movement and inhibiting the grain growth, and then improving the magnetic properties and mechanical properties. The 1.5 wt % Cu sample exhibits an excellent magnetic property with the saturation magnetization of 236.54 emu/g, which mainly attributes to the strong η, λ, Goss texture formation and the band structure optimization of Si-Cu comodification. Furthermore, the mechanical properties of the steel strip are effectively improved, and the failure plastic deformation of 1.5 wt % Cu steel strip is about 11%. The rapid solidification with Cu-dosage refinement technology also has a remarkable reference on the mechanical properties and magnetic properties modification of other metal materials.

The Manganese Peroxidase Gene Family of Trametes trogii: Gene Identification and Expression Patterns Using Various Metal Ions under Different Culture Conditions.

Manganese peroxidases (MnPs), gene family members of white-rot fungi, are necessary extracellular enzymes that degrade lignocellulose and xenobiotic aromatic pollutants. However, very little is known about the diversity and expression patterns of the MnP gene family in white-rot fungi, especially in contrast to laccases. Here, the gene and protein sequences of eight unique MnP genes of T. trogii S0301 were characterized. Based on the characteristics of gene sequence, all TtMnPs here belong to short-type hybrid MnP (type I) with an average protein length of 363 amino acids, 5-6 introns, and the presence of conserved cysteine residues. Furthermore, analysis of MnP activity showed that metal ions (Mn2+ and Cu2+) and static liquid culture significantly influenced MnP activity. A maximum MnP activity (>14.0 U/mL) toward 2,6-DMP was observed in static liquid culture after the addition of Mn2+ (1 mM) or Cu2+ (0.2 or 2 mM). Moreover, qPCR analysis showed that Mn2+ obviously upregulated the Group I MnP subfamily (T_trogii_09901, 09904, 09903, and 09906), while Cu2+ and H2O2, along with changing temperatures, mainly induced the Group II MnP subfamily (T_trogii_11984, 11971, 11985, and 11983), suggesting diverse functions of fungal MnPs in growth and development, stress response, etc. Our studies here systematically analyzed the gene structure, expression, and regulation of the TtMnP gene family in T. trogii, one of the important lignocellulose-degrading fungi, and these results extended our understanding of the diversity of the MnP gene family and helped to improve MnP production and appilications of Trametes strains and other white-rot fungi.

Characterization of the Fe-6.5wt%Si Strip with Rapid Cooling Coupling Deep Supercooled Solidification.

The phase transition law between ordered and disordered phases, second phase reinforcement, microstructure, and mechanical properties were systematically studied in the rapid cooling coupling deep supercooled solidification process through an arc melting furnace, electromagnetic induction heating, and high-speed cooling single-roll technology. The results show that uniform nucleation and grain refinement are promoted under rapid cooling coupling deep supercooled solidification, and the phase transition from the disordered phase (A2) to the ordered phase (B2 and DO3) is also effectively suppressed. The decreased crystalline grain size and optimized microstructure morphology improved the plasticity and magnetic property. The Fe-6.5wt%Si steel strip at 42 m/s has a good phase composition of Fe (predominant), Fe2Si, and SiC. The sample showed an equiaxed ferrite crystal structure, and the saturation magnetizations were 302.5 and 356.6 emu/g in the parallel magnetic direction and the vertical magnetic direction, respectively. This phase transition behavior contributed to the exceptional magnetic property of the Fe-6.5wt%Si steel.

Development of a Virtual Chinese Pediatric Population Physiological Model Targeting Specific Metabolism and Kidney Elimination Pathways.

Background: Physiologically based pharmacokinetic (PBPK) modeling and simulating may be a powerful tool in predicting drug behaviors in specific populations. It is a mathematical model that relates the pharmacokinetic (PK) profile of a compound with human anatomical characteristics, physiological characteristics, and biochemical parameters. Predictions using PBPK models offer a promising way to guide drug development and can be used to optimize clinical dosing regimens. However, PK data of new drugs in the pediatric population are too limited to guide clinical therapy, which may lead to frequent adverse events or insufficient efficacy for pediatric patients, particularly in neonates and infants. Objective: The objective of this study was to establish a virtual Chinese pediatric population based on the physiological parameters of Chinese children that could be utilized in PBPK models. Methods: A Chinese pediatric PBPK model was developed in Simcyp Simulator by collecting published Chinese pediatric physiological and anthropometric data to use as system parameters. This pediatric population model was then evaluated in the Chinese pediatric population by predicting the pharmacokinetic characteristics of four probe drugs: theophylline (major CYP1A2 substrate), fentanyl (major CYP3A4 substrate), vancomycin, and ceftazidime (renal-eliminated). Results: The predicted maximum concentration (Cmax), area under the curve of concentration-time (AUC), and clearance (CL) for theophylline (CYP1A2 metabolism pathway) and fentanyl (CYP3A4 metabolism pathway) were within two folds of the observed data. For drugs mainly eliminated by renal clearance (vancomycin and ceftazidime) in the Chinese pediatric population, the ratio of prediction to observation for major PK parameters was within a 2-fold error range. Conclusion: The model is a supplement to the previous Chinese population PBPK model. We anticipate the model to be a better representative of the pediatric Chinese population for drugs PK, offering greater clinical precision for medication given to the pediatric population, ultimately advancing clinical development of pediatric drugs. We can refine this model further by collecting more physiological parameters of Chinese children.

Physiologically based pharmacokinetic model of renally cleared antibacterial drugs in Chinese renal impairment patients.

To preliminarily develop physiologically based population models for Chinese renal impairment patients and to evaluate the prediction performance of new population models by renally cleared antibacterial drugs. First, demographic data and physiological parameters of Chinese renal impairment patients were collected, and then the coefficients of the relative demographic and physiological equation were recalibrated to construct the new population models. Second, drug-independent parameters of ceftazidime, cefodizime, vancomycin, and cefuroxime were collected and verified by Chinese healthy volunteers, Caucasian healthy volunteers, and Caucasian renal impairment population models built in Simcyp. Finally, the newly developed population models were applied to predict the plasma concentration of four antibacterial drugs in Chinese renal impairment patients. The new physiologically based pharmacokinetic (PBPK) population models can predict the main pharmacokinetic parameters, including area under the plasma concentration-time curve extrapolated to infinity (AUCinf ), renal clearance (CLr ), and peak concentration (Cmax ), of ceftazidime, cefodizime, vancomycin, and cefuroxime following intravenous administrations with less than twofold error in mild, moderate, and severe Chinese renal impairment patients. The accuracy and precision of the predictions were improved compared with the Chinese healthy volunteers and Caucasian renal impairment population models. The PBPK population models were preliminarily developed and the first-step validation results of four antibacterial drugs following intravenous administration showed acceptable accuracy and precision. The population models still need more systematic validation by using more drugs and scenarios in future studies to support their applications on dosage recommendation for Chinese renal impairment patients.

Development of a physiologically based pharmacokinetic (PBPK) population model for Chinese elderly subjects.

AIMS: This study aims to develop and verify a physiologically based pharmacokinetic (PBPK) population model for the Chinese geriatric population in Simcyp. METHODS: Firstly, physiological information for the Chinese geriatric population was collected and later employed to develop the Chinese geriatric population model by recalibration of corresponding physiological parameters in the Chinese adult population model available in Simcyp (i.e., Chinese healthy volunteer model). Secondly, drug-dependent parameters were collected for six drugs with different elimination pathways (i.e., metabolized by CYP1A2, CYP3A4 or renal excretion). The drug models were then developed and verified by clinical data from Chinese adults, Caucasian adults and Caucasian elderly subjects to ensure that drug-dependent parameters are correctly inputted. Finally, the tested drug models in combination with the newly developed Chinese geriatric population model were applied to simulate drug concentration in Chinese elderly subjects. The predicted results were then compared with the observations to evaluate model prediction performance. RESULTS: Ninety-eight per cent of predicted AUC, 95% of predicted Cmax , and 100% of predicted CL values were within two-fold of the observed values, indicating all drug models were properly developed. The drug models, combined with the newly developed population model, were then used to predict pharmacokinetics in Chinese elderly subjects aged 60-93. The predicted AUC, Cmax , and CL values were all within two-fold of the observed values. CONCLUSION: The population model for the Chinese elderly subjects appears to adequately predict the concentration of the drug that was metabolized by CYP1A2, CYP3A4 or eliminated by renal clearance.

Toward Greater Insights on Applications of Modeling and Simulation in Pregnancy.

Pregnant women are often excluded from routine clinical trials. Consequently, appropriate dosing regimens for majority of drugs are unknown in this population, which may lead to unexpected safety issue or insufficient efficacy in this un-studied population. Establishing evidence through the conduct of clinical studies in pregnancy is still a challenge. In recent decades, physiologically-based pharmacokinetic (PBPK) modeling has proven to be useful to support dose selection under various clinical scenarios, such as renal and/or liver impairment, drug-drug interactions, and extrapolation from adult to children. By integrating gestational-dependent physiological characteristics and drug-specific information, PBPK models can be used to predict PK during pregnancy. Population pharmacokinetic (PopPK) modeling approach also could complement pregnancy clinical studies by its ability to analyze sparse sampling data. In the past five years, PBPK and PopPK approaches for pregnancy have made significant progress. We reviewed recent progress, challenges and potential solutions for the application of PBPK, PopPK, and exposure-response analysis in clinical drug development for pregnancy.

Application of Physiologically-Based Pharmacokinetic Modeling to Predict Gastric pH-Dependent Drug-Drug Interactions for Weak Base Drugs.

Weak-base drugs are susceptible to drug-drug interactions (DDIs) when coadministered with gastric acid-reducing agents (ARAs). We developed PBPK models to evaluate the potential of such pH-dependent DDIs for four weak-base drugs, i.e., tapentadol, darunavir, erlotinib, and saxagliptin. The physiologically-based pharmacokinetic (PBPK) models of these drugs were first optimized using pharmacokinetic (PK) data following oral administration without ARAs, which were then verified with data from additional PK studies in the presence and absence of food. The models were subsequently used to predict the extent of DDIs with ARA coadministration. Sensitivity analysis was conducted to explore the impact of gastric pH on quantitative prediction of drug exposure in the presence of ARA. The results suggested that the PBPK models developed could adequately describe the lack of the effect of ARA on the PK of tapentadol, darunavir, and saxagliptin and could qualitatively predict the effect of ARA in reducing the absorption of erlotinib. Further studies involving more drugs with positive pH-dependent DDIs are needed to confirm the findings and broaden our knowledge base to further improve the utilization of PBPK modeling to evaluate pH-dependent DDI potential.

Synthesis and Evaluation of Bile Acid-Ribavirin Conjugates as Prodrugs to Target the Liver.

Ribavirin is used to treat hepatitis C but causes serious hemolytic anemia. The objective of the study was to develop a ribavirin prodrug to achieve liver-specific drug delivery and to reduce its off-target effect in red blood cells (RBCs). The approach aimed to target the human sodium taurocholate cotransporting polypeptide (NTCP), which is a bile acid transporter predominately expressed in the liver. Six prodrugs with ribavirin conjugation at C-3 or C-24 of the bile acids were synthesized. In vitro uptake studies indicated that all six prodrugs were NTCP substrates. Metabolic studies in vitro indicated that ribavirin-l-Val-glycochenodeoxycholic acid (GCDCA) was able to release ribavirin in the mouse liver S9 fraction. Additionally, in vitro studies showed that ribavirin in RBC was reduced by 16.7-fold from prodrug compared with parent drug incubation. Moreover, almost no prodrug was present in RBC. In vivo study in mice also showed that ribavirin-l-Val-GCDCA could provide almost the same ribavirin exposure in the liver as ribavirin administration, but with about 1.8-fold less exposure of ribavirin in RBC, plasma, and kidney. Overall, the study suggested that ribavirin-l-Val-GCDCA has the potential to achieve ribavirin-specific liver delivery.

Quantitative NTCP pharmacophore and lack of association between DILI and NTCP Inhibition.

The human sodium taurocholate cotransporting polypeptide (NTCP) is a hepatic bile acid transporter. Inhibition of NTCP uptake may potentially also prevent hepatitis B virus (HBV) infection. The first objective was to develop a quantitative pharmacophore for NTCP inhibition. Recent studies showed that hepatotoxic drugs could inhibit bile acid uptake into hepatocytes, without inhibiting canalicular efflux, and cause bile acid elevation in plasma. Hence, a second objective was to examine whether NTCP inhibition is associated with drug induced liver injury (DILI). Twenty-seven drugs from our previous study were used as the training set to develop a quantitative pharmacophore. From secondary screening from a drug database, six retrieved drugs and three drugs not retrieved by the model were tested for NTCP inhibition. Tertiary screening involved drugs known to cause DILI and not cause DILI. Overall, ninety-four drugs were assessed for hepatotoxicity and were assessed relative to NTCP inhibition. The quantitative pharmacophore possessed one hydrogen bond acceptor, one hydrogen bond donor, a hydrophobic feature, and excluded volumes. From 94 drugs, NTCP inhibitors and non-inhibitors were approximately equally distributed across the drugs of most DILI concern, less DILI concern, and no DILI concern, indicating no relationship between NTCP inhibition and DILI risk. Hence, an approach to treat HBV via NTCP inhibition is not expected to be associated with DILI.

A substrate pharmacophore for the human sodium taurocholate co-transporting polypeptide.

Human sodium taurocholate co-transporting polypeptide (NTCP) is the main bile acid uptake transporter in the liver with the capability to translocate xenobiotics. While its inhibitor requirements have been recently characterized, its substrate requirements have not. The objectives of this study were (a) to elucidate NTCP substrate requirements using native bile acids and bile acid analogs, (b) to develop the first pharmacophore for NTCP substrates and compare it with the inhibitor pharmacophores, and (c) to identify additional NTCP novel substrates. Thus, 18 native bile acids and two bile acid conjugates were initially assessed for NTCP inhibition and/or uptake, which suggested a role of hydroxyl pattern and steric interaction in NTCP binding and translocation. A common feature pharmacophore for NTCP substrate uptake was developed, using 14 native bile acids and bile acid conjugates, yielding a model which featured three hydrophobes, one hydrogen bond donor, one negative ionizable feature and three excluded volumes. This model was used to search a database of FDA approved drugs and retrieved the majority of the known NTCP substrates. Among the retrieved drugs, irbesartan and losartan were identified as novel NTCP substrates, suggesting a potential role of NTCP in drug disposition.

Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs).

The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate for OCTs and MATEs, in wild-type and Mate1-/- mice. The nephrotoxicity was assessed in the wild-type and Mate1-/- mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1-/- mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, such as ondansetron, should be investigated in patients.

Ischemia/Reperfusion-inducible protein modulates the function of organic cation transporter 1 and multidrug and toxin extrusion 1.

The recently identified ischemia/reperfusion-inducible protein (IRIP) has been reported to negatively modulate the activities of several transporters in cell culture systems. The goal of this study is to determine whether IRIP regulates the activities of OCT1 and MATE1, and hence the disposition in vivo of their substrate metformin, a therapeutic drug for diabetes and other obesity-related syndromes. In the uptake studies in the human embryonic kidney 293 cells overexpressing IRIP with and without OCT1 or MATE1, IRIP overexpression was found to significantly inhibit the uptake of 1-methyl-4-phenylpyridinium mediated by OCT1 or MATE1. In contrast, knockdown of IRIP by small hairpin RNA (shRNA) increased the transporter activities in vitro. IRIP overexpression decreased the membrane localization of transporter proteins without any changes in transcript levels in cells. By overexpressing IRIP in mouse liver via hydrodynamic tail vein injection, we demonstrated that increased IRIP expression could cause a significant reduction in hepatic accumulation of metformin (P < 0.01). In addition, we observed that the expression of IRIP was approximately half (P < 0.01) in ob/ob mice when compared to their lean littermates, with significant increases in hepatic Oct1 protein expression and metformin accumulation. In conclusion, IRIP negatively modulates the function of OCT1 and MATE1 in cells. Importantly, we provide in vivo evidence for such modulation that may cause an alteration in drug disposition. The regulation by IRIP on transporter activities likely occurs at a post-transcriptional level, and future studies are needed to characterize the exact mechanism.

Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP).

The hepatic bile acid uptake transporter sodium taurocholate cotransporting polypeptide (NTCP) is less well characterized than its ileal paralog, the apical sodium dependent bile acid transporter (ASBT), in terms of drug inhibition requirements. The objectives of this study were (a) to identify FDA approved drugs that inhibit human NTCP, (b) to develop pharmacophore and Bayesian computational models for NTCP inhibition, and (c) to compare NTCP and ASBT transport inhibition requirements. A series of NTCP inhibition studies were performed using FDA approved drugs, in concert with iterative computational model development. Screening studies identified 27 drugs as novel NTCP inhibitors, including irbesartan (Ki = 11.9 µM) and ezetimibe (Ki = 25.0 µM). The common feature pharmacophore indicated that two hydrophobes and one hydrogen bond acceptor were important for inhibition of NTCP. From 72 drugs screened in vitro, a total of 31 drugs inhibited NTCP, while 51 drugs (i.e., more than half) inhibited ASBT. Hence, while there was inhibitor overlap, ASBT unexpectedly was more permissive to drug inhibition than was NTCP, and this may be related to NTCP possessing fewer pharmacophore features. Findings reflected that a combination of computational and in vitro approaches enriched the understanding of these poorly characterized transporters and yielded additional chemical probes for possible drug-transporter interaction determinations.