A5082860873- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Animal Virus Infections Studies
- Virus-based gene therapy research
- Virology and Viral Diseases
- Immunotherapy and Immune Responses
- Viral gastroenteritis research and epidemiology
- Animal Disease Management and Epidemiology
- Immune Response and Inflammation
- interferon and immune responses
- Influenza Virus Research Studies
- Pharmacological Effects and Toxicity Studies
- Animal Genetics and Reproduction
- vaccines and immunoinformatics approaches
- Biochemical and Molecular Research
- Computational Drug Discovery Methods
- Statistical Methods in Clinical Trials
- RNA Interference and Gene Delivery
- Metabolism, Diabetes, and Cancer
- Sirtuins and Resveratrol in Medicine
- Analytical Chemistry and Chromatography
- Viral Infections and Vectors
- Viral Infections and Immunology Research
- Drug-Induced Hepatotoxicity and Protection
- Liver Disease Diagnosis and Treatment
Nanjing Agricultural University
2016-2025
Pfizer (United States)
2015-2024
Xiamen University
2004-2024
Shenzhen Center for Disease Control and Prevention
2023-2024
Tan Kah Kee Innovation Laboratory
2024
Wenzhou Medical University
2024
Fujian Agriculture and Forestry University
2012-2022
Sungkyunkwan University
2018-2021
Beijing Academy of Agricultural and Forestry Sciences
2007-2020
Jet Propulsion Laboratory
2020
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease inhibitor PF-07321332 (nirmatrelvir), in combination with ritonavir (Paxlovid), was recently granted emergency use authorization by multiple regulatory agencies for the treatment of disease 2019 (COVID-19) adults and pediatric patients. Disposition studies on nirmatrelvir animals human reagents, which were used to support clinical studies, are described herein. Plasma clearance moderate rats (27.2 ml/min per...
The present study examined the interaction of four 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (atorvastatin, lovastatin, and simvastatin in acid lactone forms, pravastatin form only) with multidrug resistance gene 1 (MDR1, ABCB1) P-glycoprotein, resistance-associated protein 2 (MRP2, ABCC2), organic anion-transporting polypeptide 1B1 (OATP1B1, <i>SLCO21A6</i>). P-glycoprotein substrate assays were performed using Madin-Darby canine kidney (MDCK) cells expressing MDR1, efflux...
The selective production of monoclonal antibodies (mAbs) reacting with defined cell surface-expressed molecules is now readily accomplished an immunological subtraction approach, surface-epitope masking (SEM). Using SEM, prostate carcinoma (Pro 1.5) mAbs have been developed that react tumor-associated antigens expressed on human cancer lines and patient-derived carcinomas. Screening a LNCaP cDNA expression library the Pro 1.5 mAb identifies gene, tumor antigen-1 (PCTA-1). PCTA-1 encodes...
Crystal structures of several urea- and thiourea-derived compounds in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein were utilized to design a potent amide-containing inhibitor bearing an aza-indole moiety (7, Nampt BC IC50 = 9.0 nM, A2780 cell proliferation 10 nM). The Nampt–7 cocrystal structure was subsequently obtained enabled additional inhibitors which incorporated various other fused 6,5-heterocyclic moieties biaryl sulfone or sulfonamide motifs. Additional...
Gemfibrozil has been suggested as a sensitive cytochrome P450 2C8 (CYP2C8) inhibitor for clinical investigation by the U.S. Food and Drug Administration European Medicines Agency. However, gemfibrozil drug-drug interactions (DDIs) are complex; its major circulating metabolite, 1-O-β-glucuronide (Gem-Glu), exhibits time-dependent inhibition of CYP2C8, both parent metabolite also behave moderate inhibitors organic anion transporting polypeptide 1B1 (OATP1B1) in vitro. Additionally, inhibit...
Myocardial injury is one of the main symptoms sepsis. However, mechanisms underlying sepsis‑induced myocardial dysfunction remain unclear. In present study, concentration cardiac troponin T (CTnT) in serum was measured using an enzyme‑linked immunosorbent assay kit. The levels interleukin (IL)‑1β and IL‑18 were assessed by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis level malondialdehyde (MDA) determined a corresponding pathology analyzed via hematoxylin...
Abstract Quantitative assessment of drug‐drug interactions (DDIs) involving breast cancer resistance protein (BCRP) inhibition is challenged by overlapping substrate/inhibitor specificity. This study used physiologically‐based pharmacokinetic (PBPK) modeling to delineate the effects inhibitor drugs on BCRP‐ and organic anion transporting polypeptide (OATP)1B‐mediated disposition rosuvastatin, which a recommended BCRP clinical probe. Initial static model analysis using in vitro data suggested...
Abstract Understanding the genetic basis of climatic adaptation is essential for predicting species’ responses to climate change. However, intraspecific variation these arising from local remains ambiguous most species. Here, we analyze genomic data diamondback moth ( Plutella xylostella ) collected 75 sites spanning six continents reveal that climate-associated adaptive exhibits a roughly latitudinal pattern. By developing an eco-genetic index combines and physiological responses, predict...
In vitro time-dependent inhibition (TDI) kinetic parameters for cytochrome P450 (P450) 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 were determined in pooled human liver microsomes 19 drugs (and two metabolites) which clinical drug-drug interactions (DDIs) are known. TDI data incorporated into the projection of magnitude DDIs using mechanistic static models Simcyp. Results suggest that model, use estimated average unbound exit concentration inhibitor from resulted a successful prediction observed was...
A sediment core spanning approximately 1,600 years was collected from a lake on Ardley Island, Antarctica. The had been greatly influenced by penguin guano. Using molecular methods, the chitinolytic bacterial community along studied over its entire length. Primers targeting conserved sequences of catalytic domains family 18 subgroup chitinases detected group wide taxonomic range bacteria. quantitative competitive PCR (QC-PCR), chitinase gene copies in each 1-cm section whole column were...
Electrospray ionization (ESI) liquid chromatography−tandem mass spectrometry (LC/MS/MS) assays provide high-throughput and selective methods for quantitation of small molecules. Use LC/MS/MS macromolecules, like oligonucleotides, is challenging due to lack sensitivity low analyte recovery from biomatrixes. Due this fact, the method choice oligonucleotides remains hybridization-based ligand-binding assays. These biological usually possess high but selectivity narrow dynamic range. They also...
Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified thiourea analogue, compound 5, as novel highly potent Nampt inhibitor. Guided by the cocrystal structure of SAR exploration revealed that corresponding urea 7 exhibited similar potency with an improved solubility profile. These studies also indicated 3-pyridyl group was preferred substituent at one inhibitor terminus and moiety optimal linker to remainder structure. Further...
Quantitative prediction of complex drug-drug interactions (DDIs) involving hepatic transporters and cytochromes P450 (P450s) is challenging. We evaluated the extent DDIs nine victim drugs-which are substrates to organic anion-transporting polypeptide 1B1 undergo metabolism or biliary elimination-caused by five perpetrator drugs, using in vitro data proposed extended net-effect model. Hepatobiliary transport metabolic clearance estimates were obtained from studies. Of total 62 clinical...
In vitro–in vivo correlation (IVIVC) of intrinsic clearance in preclinical species rat and dog was established using the hepatocyte relay method to support high-confidence prediction human pharmacokinetics for low-clearance compounds. Good IVIVC observed most compounds, with predicted values within 2-fold values. The exceptions involved transporter-mediated uptake or metabolizing enzymes extensive extrahepatic contribution. This is first assay available address low challenges drug discovery....
Herein we describe the structure-aided design and synthesis of a series pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae Escherichia coli . Rat pharmacokinetic studies compound 17 demonstrate low clearance plasma protein binding. In addition, evidence is provided for number suggesting that siderophore receptors PiuA PirA play role drug uptake P. strain PAO1.
Repaglinide is mainly metabolized by cytochrome P450 enzymes CYP2C8 and CYP3A4, it also a substrate to hepatic uptake transporter, organic anion transporting polypeptide (OATP)1B1. The purpose of this study predict the dosing time–dependent pharmacokinetic interactions repaglinide with rifampicin, using mechanistic models. In vitro transport repaglinide, characterized sandwich-cultured human hepatocytes, intrinsic metabolic parameters were used build dynamic whole-body physiologically-based...
Transmissible gastroenteritis virus (TGEV), a coronavirus, causes severe diarrhea and high mortality in newborn piglets. The porcine intestinal epithelium is the target of TGEV infection, but mechanisms that disrupts actin cytoskeleton invades host remain largely unknown. We not only found infection stimulates F-actin to gather at cell membrane disruption inhibits entry as well. Cofilin involved reorganization entry. spike protein capable binding with EGFR, activating downstream...
High-permeability-low-molecular-weight acids/zwitterions [i.e., extended clearance classification system class 1A (ECCS 1A) drugs] are considered to be cleared by metabolism with a minimal role of membrane transporters in their hepatic clearance. However, marked disconnect the vitro-in vivo (IVIV) translation is often noted for these drugs. Metabolic rates measured using human liver microsomes and primary hepatocytes tend underpredict. Here, we evaluated organic anion transporter 2...
Montelukast, a leukotriene receptor antagonist commonly prescribed for treatment of asthma, is primarily metabolized by cytochrome P450 (CYP)2C8, and has been suggested as probe substrate investigating CYP2C8 activity in vivo . We evaluated the quantitative role hepatic uptake transport its pharmacokinetics drug–drug interactions (DDIs). Montelukast was characterized with significant active human hepatocytes, showed affinity towards organic anion transporting polypeptides (OATPs) transfected...
Hepatic impairment (HI) is known to modulate drug disposition and may lead elevated plasma exposure. The aim of this study was quantitate the in vivo OATP1B-mediated hepatic uptake activity populations with varying degrees HI. First, we measured baseline levels coproporphyrin-I, an endogenous OATP1B biomarker, open-label, parallel cohort adult subjects normal liver function mild, moderate, severe HI (n = 24, 6/cohort). geometric mean concentrations coproporphyrin-I were 1.66-fold, 2.81-fold...
Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family kinases with high degree selectivity within human genome's set protein kinases. Currently approved formulations for tofacitinib citrate are immediate‐release (IR) tablets, modified‐release (MR) and IR solution. A once daily MR microsphere formulation was developed use in pediatric patients. Demonstration bioequivalence (BE) between 10 mg (q.d.) 5 twice (b.i.d.) solution needed to enable exposure–response...