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Related Concept Videos

Hepatic Drug Excretion: Enterohepatic Cycling01:17

Hepatic Drug Excretion: Enterohepatic Cycling

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Enterohepatic cycling involves the active secretion of drugs and their metabolites into the bile via transporters in the canalicular membrane of hepatocytes. This secretion is an integral part of the digestive process, releasing these substances into the gastrointestinal (GI) tract.
Post-release drugs and metabolites can be reabsorbed into the body from the intestine. For conjugated metabolites like glucuronides, reabsorption requires enzymatic hydrolysis by intestinal microflora. This...
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Diarrhea-predominant irritable bowel syndrome (IBS-D) is a subtype of IBS characterized primarily by frequent, loose, or watery stools, abdominal pain, and abdominal discomfort. Therapeutic approaches to managing IBS-D include dietary changes, stress management techniques, and pharmaceutical interventions.
Two specific drugs used in the treatment are alosetron (Lotronex) and eluxadoline (Viberzi). Alosetron, a 5-HT3 antagonist, works by slowing the movement of stools in the gut, reducing bowel...
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Dipeptidyl Peptidase 4 Inhibitors01:23

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Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a...
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Bioavailability Enhancement: Drug Permeability Enhancement01:27

Bioavailability Enhancement: Drug Permeability Enhancement

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Body:After oral administration, poor permeability often limits the rate at which drugs are absorbed through the intestinal epithelium. Enhancing drug permeability is crucial for effective therapy, and several strategies have been developed to overcome this challenge.One effective strategy involves the use of lipid-based formulations. These formulations enhance dissolution and solubility, targeting physiological mechanisms to increase drug absorption. This includes stimulating bile salt...
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Hepatic Drug Clearance: Role of Transporters01:14

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In the liver and bile canaliculi, influx and efflux transporters modification can influence intrinsic clearance. Transporters play a significant role in moving drugs within liver cells. Elaborate models, such as the Biopharmaceutical Classification System (BCS), are essential to relate transporters to drug disposition. This system categorizes drugs into four classes based on solubility and permeability, providing insights into elimination routes and the effects of transporters following oral...
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Hyperlipidemia, a medical condition often referred to as high cholesterol, is characterized by abnormally elevated levels of lipids in the bloodstream. When present in excess, these lipids, specifically cholesterol and triglycerides, can lead to serious health complications, often involving cardiovascular diseases. Illnesses like atherosclerosis, heart attacks, and pancreatitis have all been linked to untreated hyperlipidemia. This means controlling and regulating cholesterol and triglyceride...
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A Competent Hepatocyte Model Examining Hepatitis B Virus Entry through Sodium Taurocholate Cotransporting Polypeptide as a Therapeutic Target
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Hepatitis D Virus Entry Inhibitors Based on Repurposing Intestinal Bile Acid Reabsorption Inhibitors.

Michael Kirstgen1, Kira Alessandra Alicia Theresa Lowjaga1, Simon Franz Müller1

  • 1Institute of Pharmacology and Toxicology, Biomedical Research Center Seltersberg (BFS), Faculty of Veterinary Medicine, Justus Liebig University Giessen, Schubertstr. 81, 35392 Giessen, Germany.

Viruses
|April 30, 2021
PubMed
Summary
This summary is machine-generated.

Researchers screened bile acid reabsorption inhibitors to find new Hepatitis B and D virus (HBV/HDV) entry blockers. They identified compounds that inhibit HBV/HDV entry more effectively than bile acid transport, offering potential for selective antiviral therapies.

Keywords:
ASBTHBVHDVNTCPbile acid transportentry inhibitorstructure-activity relationship

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Area of Science:

  • Hepatology
  • Virology
  • Drug Discovery

Background:

  • Hepatitis B and D viruses (HBV/HDV) utilize the Na+/taurocholate co-transporting polypeptide (NTCP) as a hepatic entry receptor.
  • Existing HBV/HDV entry inhibitors often disrupt NTCP's physiological bile acid transport function.

Purpose of the Study:

  • To identify novel, virus-selective NTCP inhibitors.
  • To repurpose bile acid reabsorption inhibitors (BARIs) as potential HBV/HDV entry blockers.

Main Methods:

  • Screening of 87 propanolamine derivatives for NTCP binding and taurocholic acid transport inhibition.
  • In vitro validation of anti-HDV activity in NTCP-HepG2 cells.
  • Analysis of structure-activity relationships for virus selectivity.

Main Results:

  • Three compounds (S985852, A000295231, S973509) demonstrated potent in vitro anti-HDV activity (IC50: 15-70 µM).
  • These compounds exhibited significantly higher IC50 values for taurocholic acid uptake inhibition (24-780 µM), indicating selectivity.
  • Structure-activity relationship analysis suggested potential for optimizing virus selectivity.

Conclusions:

  • Repurposing BARIs is a viable strategy for developing novel HBV/HDV entry inhibitors.
  • Achieving virus selectivity over bile acid transport function is possible through structural modifications.