DRUG METABOLISM AND DISPOSITION
·
2016
·Vol. 44
·期 1
·40-49
·
IF 3.21
Ning Zhou,Yuanting Zheng,Junfen Xing,Huiying Yang,Hanmei Chen,Xiaoqiang Xiang,Jing Liu,Shanshan Tong,Bin Zhu,Weimin Cai
Currently used in vitro models for estimating liver metabolism do not take into account the physiologic structure and blood circulation process of liver tissue. The Bio-PK metabolic system was established as an alternative approach to determine the in vitro intrinsic clearance of the model drug tolbutamide. The system contained a peristaltic pump, recirculating pipeline, reaction chamber, and rat liver microsomes (RLMs) encapsulated in pluronic F127-acrylamide-bisacrylamide (FAB) hydrogel. The metabolism of tolbutamide at initial concentrations of 100, 150, and 200 μM was measured in both the FAB hydrogel and the circular medium. The data from the FAB hydrogel and the circular medium were fitted to a mathematical model to obtain the predicted intrinsic clearance of tolbutamide after different periods of preincubation. The in vitro clearance value for tolbutamide was incorporated into Simcyp software and used to predict both the in vivo clearance value and the dynamic process of elimination. The predicted in vivo clearance of tolbutamide was 0.107, 0.087, and 0.095 L/h/kg for i.v. injection and 0.113, 0.095, and 0.107 L/h/kg for oral administration. Compared with the reported in vivo clearance of 0.09 L/h/kg (i.v.) and 0.10 L/h/kg (oral), all the predicted values differed by less than twofold. Thus, the Bio-PK metabolic system is a reliable and general in vitro model, characterized by three-dimensional structured RLM and circulation and perfusion processes for predicting the in vivo intrinsic clearance of low-extraction compounds, making the system more analogous with the rat in terms of both morphology and physiology
研究领域:
药代动力学
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药物代谢
·
生物医学工程
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2015
·
IF 2.979
Min Liao,Cong Dai,Mengping Liu,Jiefeng Chen,Zuanguang Chen,Zhiyong Xie,Meicun Yao
A novel, sensitive and rapid ultra-performance liquid chromatography–tandem mass spectrometric (UPLC–MS/MS) method for simultaneous quantification of four furostanol glycosides in rat plasma was established and validated. Ginsenoside Rb1 was used as an internal standard. Plasma samples were pretreated by liquid–liquid extraction with n -butanol and chromatographed on a C18 column (2.1 × 50 mm i.d., 2.6 μm) using a gradient elution program consisting of acetonitrile and water (containing 0.03% formic acid and 0.1 mM lithium acetate) at a flow rate of 0.4 mL/min. Lithium adduct ions were employed to enhance the response of the analytes in electrospray positive ionization mode and multiple reaction monitoring transitions were performed for detection. All calibration curves exhibited good linearity ( r > 0.999) over the range of 10–20,000 ng/mL for protodioscin and 2–4000 ng/mL for protogracillin, pseudoprotodioscin and pseudoprotogracillin. The recoveries of the whole analytes were more than 80.3% and exhibited no severe matrix effect. Meanwhile, the intra- and inter-day precisions were all less than 10.7% and accuracies were within the range of −8.1–12.9%. The four saponins showed rapid excretion and relative high plasma concentrations when the validated method was applied to the PK study of Dioscorea nipponica extracts by intragastric administration at low, medium and high dose to rats. Moreover, the T 1/2 and AUC 0– t of each compound turned out to behave in a dose-dependent pattern by comparing them at different dose levels.
研究领域:
分析化学
·
药理学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Yanmei Shi,Liqin Chao,Xiaobing Liu,Zhihong Chen,Zhenghui Chang,Sisen Zhang,Shusheng Zhang,Kai Hu
Development of advanced in vivo sampling tools for the synchronous monitoring of drugs and endogenous biomarkers is critical for integrated pharmacokinetic-pharmacodynamic (PK-PD) studies. Herein, a novel solid-phase microextraction (SPME) fiber coating was engineered based on a zwitterionic covalent organic framework (EB-TTB-DABSA COF), strategically functionalized with sulfonate and quaternary ammonium groups. This rationally designed coating provides synergistic electrostatic, π–π, and hydrophobic interactions, enabling the efficient and simultaneous extraction of both cationic alkaloids and neurotransmitters. Coupled with LC-MS/MS, the developed platform achieved highly sensitive (limits of detection down to 3.3 × 10 −3 ng·mL −1 ), minimally invasive, and synchronous monitoring of these analytes in paired blood and brain matrices of living rats. Application in a Parkinson's disease (PSD) model revealed altered pharmacokinetics of Coptis chinensis alkaloids, including significantly increased area under the curve (AUC) values ( p < 0.01) and prolonged elimination half-lives compared to controls. These findings indicate enhanced systemic absorption and improved bioavailability of alkaloids under PSD conditions. Crucially, pharmacodynamic analysis showed that alkaloid administration triggered a synchronized restoration of key depleted neurotransmitters in PSD brains. A correlation with a characteristic hysteresis pattern further established a delayed neuroprotective relationship between alkaloid concentrations and neurotransmitter levels. This study not only introduces a robust zwitterionic COF-SPME platform for concurrent in vivo biosampling but also provides the first quantitative neuropharmacological perspective on Coptis chinensis alkaloids, offering a foundational framework for mechanistic research and therapeutic development in PSD.
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DOI
高影响因子
BMC Pharmacology & Toxicology
·
2024
·Vol. 25
·期 1
·1-15
·
IF 2.8
Wang Tianyan,Tao Ting,Liu Yi,Dong Jie,Ni Shanhong,Liu Yun,Li Yanli,Xu Ning,Sun Zengxian
Background and purposes It is unclear whether the parent Saxagliptin (SAX) in vivo is the same as that in vitro, which is twice that of 5-hydroxy Saxagliptin (5-OH SAX). This study is to construct a Pharmacokinetic-Pharmacodynamic (PK-PD) link model to evaluate the genuine relationship between the concentration of parent SAX in vivo and the effect. Methods First, we established a reliable Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) method and DPP-4 inhibition ratio determination method. Then, the T2DM rats were randomly divided into four groups, intravenous injection of 5-OH SAX (0.5 mg/kg) and saline group, intragastric administration of SAX (10 mg/kg) and Sodium carboxymethyl cellulose (CMC-Na) group. Plasma samples were collected at different time points for subsequent testing. Finally, we used the measured concentrations and inhibition ratios to construct a PK-PD link model for 5-OH SAX and parent SAX. Results A two-compartment with additive model showed the pharmacokinetic process of SAX and 5-OH SAX, the concentration-effect relationship was represented by a sigmoidal E max model and sigmoidal E max with E 0 model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration ( T max =0.11 h, t 1/2, ka =0.07 h), widely distributed in the body (V ≈ 20 L/kg), plasma exposure reached 3282.06 ng*h/mL, and the elimination half-life was 6.13 h. The maximum plasma dipeptidyl peptidase IV (DPP-4) inhibition ratio of parent SAX was 71.47%. According to the final fitting parameter EC 50 , EC 50, 5−OH SAX =0.46EC 50, SAX(parent) , it was believed that the inhibitory effect of 5-OH SAX was about half of the parent SAX, which is consistent with the literature. Conclusions The PK-PD link model of the parent SAX established in this study can predict its pharmacokinetic process in T2DM rats and the strength of the inhibitory effect of DPP-4 based on non-clinical data.
研究领域:
药理学
·
药代动力学
·
药效学
·
糖尿病研究
·
分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2018
·Vol. 39
·期 9
·1522-1532
·
IF 3.562
Xue Cai-fu,Zhang Zhe,Jin Yan,Zhu Bin,Xing Jun-fen,Ma Guo,Xiang Xiao-qiang,Cai Wei-min
Liver metabolism is commonly considered the major determinant in drug discovery and development. Many in vitro drug metabolic studies have been developed and applied to understand biotransformation. However, these methods have disadvantages, resulting in inconsistencies between in vivo and in vitro experiments. A major factor is that they are static systems that do not consider the transport process in the liver. Here we developed an in vitro dynamic metabolic system (Bio-PK metabolic system) to mimic the human pharmacokinetics of tolbutamide. Human liver microsomes (HLMs) encapsulated in a F127'-Acr-Bis hydrogel (FAB hydrogel) were placed in the incubation system. A microdialysis sampling technique was used to monitor the metabolic behavior of tolbutamide in hydrogels. The measured results in the system were used to fit the in vitro intrinsic clearance of tolbutamide with a mathematical model. Then, a PBPK model that integrated the corresponding in vitro intrinsic clearance was developed to verify the system. Compared to the traditional incubation method, reasonable PK profiles and the in vivo clearance of tolbutamide could be predicted by integrating the intrinsic clearance of tolbutamide obtained from the Bio-PK metabolic system into the PBPK model. The predicted maximum concentration ( C
max ), area under the concentration-time curve (AUC), time to reach the maximum plasma concentration ( T
max ) and in vivo clearance were consistent with the clinically observed data. This novel in vitro dynamic metabolic system can compensate for some limitations of traditional incubation methods; it may provide a new method for screening compounds and predicting pharmacokinetics in the early stages, supporting the development of compounds.
研究领域:
药理学
·
药物代谢
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF GENERAL VIROLOGY
·
2024
·Vol. 105
·期 5
·001996
·
IF 3.6
Yuting Duan,Haichuan Li,Shuai Huang,Yaoming Li,Shuyi Chen,Lilan Xie
Transmissible gastroenteritis virus (TGEV), an enteropathogenic coronavirus, has caused huge economic losses to the pig industry, with 100% mortality in piglets aged 2 weeks and intestinal injury in pigs of other ages. However, there is still a shortage of safe and effective anti-TGEV drugs in clinics. In this study, phloretin, a naturally occurring dihydrochalcone glycoside, was identified as a potent antagonist of TGEV. Specifically, we found phloretin effectively inhibited TGEV proliferation in PK-15 cells, dose-dependently reducing the expression of TGEV N protein, mRNA, and virus titer. The anti-TGEV activity of phloretin was furthermore refined to target the internalization and replication stages. Moreover, we also found that phloretin could decrease the expression levels of proinflammatory cytokines induced by TGEV infection. In addition, we expanded the potential key targets associated with the anti-TGEV effect of phloretin to AR, CDK2, INS, ESR1, ESR2, EGFR, PGR, PPARG, PRKACA, and MAPK14 with the help of network pharmacology and molecular docking techniques. Furthermore, resistant viruses have been selected by culturing TGEV with increasing concentrations of phloretin. Resistance mutations were reproducibly mapped to the residue (S242) of main protease (Mpro). Molecular docking analysis showed that the mutation (S242F) significantly disrupted phloretin binding to Mpro, suggesting Mpromight be a potent target of phloretin. In summary, our findings indicate that phloretin is a promising drug candidate for combating TGEV, which may be helpful for developing pharmacotherapies for TGEV and other coronavirus infections.
研究领域:
病毒学
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药理学
·
分子生物学
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DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2023
·Vol. 8
·期 1
·1-16
·
IF 39.3
Cui Bopei,Song Lifang,Wang Qian,Li Kelei,He Qian,Wu Xing,Gao Fan,Liu Mingchen,An Chaoqiang,Gao Qiushuang,Hu Chaoying,Hao Xiaotian,Dong Fangyu,Zhou Jiuyue,Liu Dong,Song Ziyang,Yan Xujia,Zhang Jialu,Bai Yu,Mao Qunying,Yang Xiaoming,Liang Zhenglun
With the continuous in-depth study of the interaction mechanism between viruses and hosts, the virus has become a promising tool in cancer treatment. In fact, many oncolytic viruses with selectivity and effectiveness have been used in cancer therapy. Human enterovirus is one of the most convenient sources to generate oncolytic viruses, however, the high seroprevalence of some enteroviruses limits its application which urges to exploit more oncolytic enteroviruses. In this study, coxsackievirus B5/Faulkner (CV-B5/F) was screened for its potential oncolytic effect against non-small cell lung cancers (NSCLCs) through inducing apoptosis and autophagy. For refractory NSCLCs, DNA-dependent protein kinase (DNA-PK) or ataxia telangiectasia mutated protein (ATM) inhibitors can synergize with CV-B5/F to promote refractory cell death. Here, we showed that viral infection triggered endoplasmic reticulum (ER) stress-related pro-apoptosis and autophagy signals, whereas repair for double-stranded DNA breaks (DSBs) contributed to cell survival which can be antagonized by inhibitor-induced cell death, manifesting exacerbated DSBs, apoptosis, and autophagy. Mechanistically, PERK pathway was activated by the combination of CV-B5/F and inhibitor, and the irreversible ER stress-induced exacerbated cell death. Furthermore, the degradation of activated STING by ERphagy promoted viral replication. Meanwhile, no treatment-related deaths due to CV-B5/F and/or inhibitors occurred. Conclusively, our study identifies an oncolytic CV-B5/F and the synergistic effects of inhibitors of DNA-PK or ATM, which is a potential therapy for NSCLCs.
研究领域:
肿瘤学
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病毒学
·
分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
Frontiers in Veterinary Science
·
2021
·
IF 3.412
Ahmad Salah Uddin,Sun Jichao,Cheng Fusheng,Li Bing,Arbab Safia,Zhou Xuzheng,Zhang Jiyu
A comparative study on pharmacokinetics of four long-acting enrofloxacin injectable formulations was investigated in 36 healthy pigs after intramuscular injection according to the recommended single dose @ 2.5 mg/kg body weight. The drug concentrations in the plasma were computed using high-performance liquid chromatography (HPLC) with fluorescence detection. WinNonLin5.2.1 software was used to analyze the experimental data and compared it under one-way ANOVA using SPSS software with a 95% confidence interval (CI). The main pharmacokinetic parameters, that is, the maximum plasma concentrations (Cmax), the time to maximum concentration (Tmax), area under the time curve concentration (AUCall) and Terminal half-life (T1/2) were 733.84 ± 129.87, 917.00 ± 240.13, 694.84 ± 163.49, 621.98 ± 227.25 ng/ml, 2.19 ± 0.0.66, 1.50 ± 0.37, 2.89 ± 0.24, 0.34 ± 0.13 h, 7754.43 ± 2887.16, 8084.11 ± 1543.98, 7369.42 ± 2334.99, 4194.10 ± 1186.62 ng h/ml, 10.48 ± 2.72, 10.37 ± 2.38, 10.20 ± 2.81, and 10.61 ± 0.86 h for 10% enrofloxacin (Alkali), 20% enrofloxacin (Acidic), Yangkang and control drug Nuokang® respectively. There were significant differences among Cmax, Tmax, and AUCall of three formulations compare with that of the reference formulation. No significant differences were observed among the T1/2 for tested formulations compare with the reference formulation. The pharmacokinetic parameters showed that the tested formulations were somewhat better compared to the reference one. The calculated PK/PD indices were effective for bacteria such as Actinobacillus pleuropneumoniae and Pasteurella multocida with values higher than the cut-off points (Cmax/MIC90≥10–12 and AUC/MIC90 ≥ 125). However, they were not effective against bacteria like Haemophilus parasuis, Streptococcus suis, E. coli, and Bordetella bronchiseptica where lower values were obtained.
研究领域:
药理学
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兽医学
·
动物科学
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产品关联
DOI
PubMed
高影响因子
MICROBIAL PATHOGENESIS
·
2024
·
IF 3.3
Xiaoye Cheng,Yijin Jiang,Xu Zhao,Nana Ma,Xiangzhen Shen
Lactate has been increasingly recognized for its role in diseases progression, necessitating a deeper understanding of its metabolic processes and regulatory mechanisms. This study aimed to evaluate the impact of lipopolysaccharide (LPS) on lactate accumulation in bovine mammary epithelial cells (BMECs) and to elucidate the underlying regulatory mechanisms. Further optimization of LPS treatment points was achieved by assessing the content of key glycolytic enzymes-hexokinases (HK), pyruvate kinase (PK) and pyruvate dehydrogenase (PDH)-as well as the expression levels of HK2, pyruvate dehydrogenase kinase4 (PDK4) and lactate dehydrogenase (LDHA). Our results indicate that LPS can promote intracellular glycolysis and inhibits pyruvate synthesis, thereby increasing lactate content. BMECs were cultured and divided into a control group (CON) and an LPS-stimulated group (10 μg/mL for 6 h, LPS group). LPS was found to upregulate expression levels of HIF-1α and MCT1, suggesting a role for HIF-1α and MCT1 in cellular glucose metabolism. To explore the effect of HIF-1α on lactate accumulation, BMECs were stimulated with a HIF-1α inducer (COCL 2 ) and HIF-1α inhibitor (DMBPA). COCL 2 was observed to promote lactate accumulation, while DMBPA inhibited it. Additionally, modulation of HIF-1α expression influenced the expression of MCT1, which is a crucial transporter for extracellular lactate influx. To investigate the specific impact of MCT1 on intracellular lactate, we utilized overexpression plasmids and small interfering RNA to modulate MCT1 expression. The findings indicate that while MCT1 expression alone does not affect intracellular lactate levels, it does modulate the changes induced by LPS. In conclusion, our study suggests that LPS regulates lactate accumulation in BMECs through the HIF-1α/MCT1 pathway, providing insights into the metabolic dysregulation associated with LPS-induced stress in dairy cattle.
研究领域:
动物科学
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细胞生物学
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代谢学
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乳品科学
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产品关联
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2023
·
IF 4.7
Yuecheng Zhao,Chuanshan Zou,Lu Zhang,Chengde Li,Xingpeng Li,Liwen Song
Chlorbenzuron is a kind of benzoylphenylureas (BPUs), which plays a broad role in insect growth regulators (IGRs), with an inhibitory effect on chitin biosynthesis. However, BPUs how to regulate glycolysis and insect growth remains largely unclear. Here, we investigated the effects of chlorbenzuron on growth, nutritional indices, glycolysis, and carbohydrate homeostasis in Hyphantria cunea , a destructive and highly polyphagous forest pest, to elucidate the action mechanism of chlorbenzuron from the perspective of energy metabolism. The results showed that chlorbenzuron dramatically restrained the growth and nutritional indices of H. cunea larvae and resulted in lethality. Meanwhile, we confirmed that chlorbenzuron significantly decreased carbohydrate levels, adenosine triphosphate (ATP), and pyruvic acid (PA) in H. cunea larvae. Further studies indicated that chlorbenzuron caused a significant enhancement in the enzyme activities and mRNA expressions of hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK), resulting in increased glycolytic flux. Expressions of genes involved in the AMP-activated protein kinase (AMPK) signaling pathway were also upregulated. Moreover, chlorbenzuron had remarkable impacts on H. cunea larvae from the perspective of metabolite enrichment, including the tricarboxylic acid (TCA) cycle and glycolysis, indicating an energy metabolism disorder in larvae. The findings provide a novel insight into the molecular mechanism by which chlorbenzuron abnormally promotes glycolysis and eventually interferes with insect growth and nutritional indices.
研究领域:
昆虫学
·
生物化学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2022
·
IF 5.195
Xu-guang Zhang,Ai-xia Liu,Yu-xin Zhang,Ming-yan Zhou,Xiang-yi Li,Ming-hai Fu,Yi-peng Pan,Jian Xu,Jun-qing Zhang
Ethnopharmacological relevance Alpinia officinarum Hance, a perennial natural medicine-food herb, has been traditionally used to treat colds, stomachache, and diabetes for thousands of years. 1,7-Diphenyl-4E-en-3-heptanone (DPH5), a diarylheptanoid isolated from the rhizome of A. officinarum has been reported to be safe and to have antioxidant and hypoglycemic effects, suggesting its potential in the treatment of insulin resistance (IR). Aim of the study : Aim of to investigate the protective effect of DPH5 on IR and elucidate its underlying mechanism of action. Materials and methods HepG2 cells were used as the research objects. Glucose uptake and reactive oxygen species (ROS) levels in high glucose–induced insulin-resistant HepG2 cells were assessed using flow cytometry. Glucose consumption and the levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were analyzed using the corresponding assay kits. The expression of mRNA and proteins related to insulin signaling, glucose metabolism, and antioxidant factor, including insulin receptor substrate-1 (IRS1), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), translocation of glucose transporter-4, glycogen synthase kinase-3β (GSK3β), glucokinase (GCK), pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), nuclear factor-erythroid 2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NADPH quinoneoxidoreductase (NQO1), and glutathione peroxidase (GSH-Px) was determined using real-time quantitative polymerase chain reaction and western blotting . Furthermore, molecular docking was performed to determine the spatial mechanism of DPH5 on the key targets PI3K, AKT, Nrf2 , and GSK3β. Results DPH5 could improve IR that manifested as increased glucose uptake and glucose consumption in insulin-resistant HepG2 cells. Moreover, DPH5 could enhance antioxidant capacity by activating Nrf2/HO-1 elements, including increasing Nrf2, HO-1, SOD, NQO1, and GSH-Px expression and reducing MDA, ROS, and JNK levels, thereby improving oxidative stress and ultimately alleviating IR. Additionally, DPH5 could promote the expression of IRS1, PI3K, AKT, GSK3β, GCK, and PK, and downregulate the expression of PEPCK and G6pase, thereby accelerating glucose utilization and enhancing insulin sensitivity. The mechanism underlying the effect of DPH5 in alleviating IR was related to the PI3K/AKT- and Nrf2/HO-1-mediated regulation of the GSK3β signaling pathway, and the results were further confirmed using the specific inhibitors LY294002 and ML385. Results from molecular docking indicated that there were different regulatory sites and interacting forces between DPH5 and PI3K, AKT, Nrf2, and GSK3β; however, the binding force was relatively strong. Conclusions DPH5 improved oxidative stress and glucose metabolism via modulating the PI3K/AKT-Nrf2-GSK3β pathway, thereby ameliorating IR. Overall, our findings suggest the potential of DPH5 as a natural medicine to treat type-2 diabetes mellitus.
研究领域:
药理学
·
细胞生物学
·
分子生物学
·
内分泌学
·
糖尿病
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）