A5021669705- Drug Transport and Resistance Mechanisms
- Pharmacological Effects and Toxicity Studies
- Folate and B Vitamins Research
- Alcoholism and Thiamine Deficiency
- Amino Acid Enzymes and Metabolism
- Metabolism and Genetic Disorders
- Pharmacogenetics and Drug Metabolism
- Lipid metabolism and disorders
- Immunodeficiency and Autoimmune Disorders
- Liver Disease Diagnosis and Treatment
- Monoclonal and Polyclonal Antibodies Research
- Multiple Myeloma Research and Treatments
- Diabetes Treatment and Management
- Computational Drug Discovery Methods
- DNA and Nucleic Acid Chemistry
- Chromatin Remodeling and Cancer
- Metabolism, Diabetes, and Cancer
- Glycosylation and Glycoproteins Research
- Single-cell and spatial transcriptomics
- Diet, Metabolism, and Disease
- Adenosine and Purinergic Signaling
- 3D Printing in Biomedical Research
- Antibiotics Pharmacokinetics and Efficacy
- Protein Degradation and Inhibitors
- Pluripotent Stem Cells Research
Medical College of Wisconsin
2024
Taipei Medical University
2024
University of California, San Francisco
2014-2018
Tsinghua University
2015
University of California System
2015
Significance This manuscript describes a previously unidentified mechanism for organic cation transporter 1 (OCT1), the major hepatic metformin transporter, in steatosis. Here we show that OCT1, long thought to function primarily as drugs, functions thiamine liver, which has profound implications cellular metabolism. Collectively, our results point an important role of (through OCT1) steatosis and suggest modulation disposition by may contribute its pharmacologic effects.
The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH's, transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic transporter 1, OCT1, hepatic uptake metformin, was also primary thiamine, vitamin B1. In this study, we tested reverse, i.e., substrate thiamine transporters (THTR-1, SLC19A2, THTR-2, SLC19A3). Our study...
Metformin, the most widely prescribed antidiabetic drug, requires transporters to enter tissues involved in its pharmacologic action, including liver, kidney, and peripheral tissues. Organic cation transporter 3 (OCT3, <i>SLC22A3</i>), expressed ubiquitously, transports metformin, but vivo role metformin response is not known. Using <i>Oct3</i> knockout mice, of pharmacokinetics pharmacodynamics was determined. After an intravenous dose a 2-fold decrease apparent volume distribution...
Abstract Background Proteolysis-targeting chimeras (PROTACs) are being developed for therapeutic use. However, they have poor pharmacokinetic profiles and their tissue distribution kinetics not known. Methods A typical von Hippel-Lindau tumor suppressor (VHL)—PROTAC 14 C-A947 (BRM degrader)—was synthesized its was studied by quantitative whole-body autoradiography (QWBA) excision in rats following IV dosing. Bile duct-cannulated (BDC) allowed the elucidation of vivo clearance pathways....
Organic cation transporter 1 (OCT1) plays a critical role in the hepatocellular uptake of structurally diverse endogenous compounds and xenobiotics. Here we identified competitive noncompetitive OCT1-interacting ligands library 1780 prescription drugs by combining silico vitro methods. Ligands were predicted docking against comparative model based on eukaryotic homologue. In parallel, high-throughput screening (HTS) was conducted using fluorescent probe substrate ASP+ cells overexpressing...
A constellation of metabolic disorders, including obesity, dysregulated lipids, and elevations in blood glucose levels, has been associated with cardiovascular disease diabetes. Analysis data from recently published genome-wide association studies (GWAS) demonstrated that reduced-function polymorphisms the organic cation transporter, OCT1 (SLC22A1), are significantly higher total cholesterol, low-density lipoprotein (LDL) triglyceride (TG) levels an increased risk for type 2 diabetes...
IgA antibodies have broad potential as a novel therapeutic platform based on their superior receptor-mediated cytotoxic activity, potent neutralization of pathogens, and ability to transcytose across mucosal barriers via polymeric immunoglobulin receptor (pIgR)-mediated transport, compared traditional IgG-based drugs. However, the transition into clinical development has been challenged by complex expression characterization, well rapid serum clearance that is thought be mediated glycan...
Permeability assays are commonly conducted with Madin-Darby canine kidney (MDCK) cells to predict the intestinal absorption of small-molecule drug candidates. In addition, MDCK transfected overexpress efflux transporters often used identify substrates. However, exhibit endogenous activity for a significant proportion experimental compounds, potentially leading underestimation permeability and confounded findings in transport studies. The goal this study was evaluate Mdr1 knockout (gMDCKI)...
The organic cation transporter 3 (OCT3, SLC22A3) is ubiquitously expressed and interacts with a wide array of compounds including endogenous molecules, environmental toxins prescription drugs. Understudied as determinant pharmacokinetics pharmacodynamics, OCT3 has the potential to be major drug absorption disposition target for drug-drug interactions (DDIs).The goal current study was identify inhibitors OCT3.We screened compound library consisting 2556 drugs, bioactive natural products using...
Abstract GDC‐0810 was under development as an oral anti‐cancer drug for the treatment of estrogen receptor‐positive breast cancer a single agent or in combination. In vitro data indicated that is potent inhibitor OATP1B1/1B3. To assess clinical risk, PBPK model developed to predict transporter drug–drug interaction (tDDI) between and pravastatin human. The constructed Simcyp® by integrating vivo GDC‐0810. prediction human pharmacokinetics (PK) verified using phase I PK data. Simcyp DDI known...
Patients with chronic kidney disease (CKD) have a high incidence of dyslipidemia comprising triglyceride (TG) and low high-density lipoprotein (HDL)-cholesterol levels. An abnormal increase TGs within cells can lead to intracellular lipid accumulation. In addition dyslipidemia, hyperglycemia in diabetes may elicit ectopic deposition non-adipose tissues. Hyperglycemia increases levels methylglyoxal (MG) leading cellular dysfunction. A deficit glyoxalase I (GLO1) contributes dicarbonyl stress....