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Related Concept Videos

Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters01:16

Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters

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The pharmacogenetics of drug transporters is increasingly recognized as a critical factor influencing interindividual variability in drug absorption, distribution, and elimination. These membrane-bound proteins regulate drugs' movement across cellular barriers by actively pumping them out (efflux) or facilitating their uptake (influx). Among the major transporter families, ATP-binding cassette (ABC) and solute carrier (SLC) transporters play particularly prominent roles. Genetic polymorphisms...
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Carrier-Mediated Transport01:06

Carrier-Mediated Transport

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Carrier-mediated transport is a pivotal process in drug absorption, particularly for lipid-insoluble drugs, and encompasses facilitated diffusion and active transport. Facilitated diffusion allows drugs to move along their concentration gradient without energy expenditure, while active transport utilizes ATP to drive drug movement against this gradient.
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
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Hepatic Drug Clearance: Effect of Protein Binding01:09

Hepatic Drug Clearance: Effect of Protein Binding

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Hepatic clearance is influenced by protein binding based on the drug's extraction ratio. Drugs with high extraction ratios are considered flow-limited and remain unaffected by protein binding during hepatic clearance. On the other hand, drugs with low extraction ratios may be impacted by plasma protein binding, although the extent of this influence depends on the fraction of the drug bound.
For low-extraction-ratio drugs that are less than 80% protein-bound, minor changes in protein binding...
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Drug Absorption Mechanism: Carrier-Mediated Membrane Transport01:19

Drug Absorption Mechanism: Carrier-Mediated Membrane Transport

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Certain large, lipid-insoluble drug molecules that resemble amino acids, peptides, or glucose, require specialized carrier proteins to facilitate their diffusion across cell membranes. This transport can occur through either facilitated diffusion, which does not require energy input, or active transport, which does require energy input.
Facilitated diffusion is a passive process that utilizes human Solute Carrier (SLC) transporters. These transporters bind to the drug, undergo structural...
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Hepatic Drug Clearance: Role of Transporters01:14

Hepatic Drug Clearance: Role of Transporters

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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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GPCR Desensitization01:12

GPCR Desensitization

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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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Related Experiment Video

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Concanavalin A-Based Sedimentation Assay to Measure Substrate Binding of Glucan Phosphatases
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Convallatoxin: a new P-glycoprotein substrate.

Elnaz Gozalpour1, Rick Greupink1, Albert Bilos1

  • 1Department of Pharmacology and Toxicology 149, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

European Journal of Pharmacology
|September 30, 2014
PubMed
Summary
This summary is machine-generated.

Convallatoxin, a Lily of the Valley toxin, is a new substrate for P-glycoprotein (P-gp), a key drug transporter. This finding clarifies interactions between digitalis-like compounds and P-gp, impacting drug safety.

Keywords:
ConvallatoxinConvallatoxin (Pubchem CID: 441852)Cymarin (Pubchem CID: 539061)Digitalis-like compoundsDigitoxigenin (Pubchem CID: 4369270)Digitoxin (Pubchem CID: 441207)Digoxigenin (Pubchem CID: 15478)Digoxin (Pubchem CID: 2724385)Lily of the ValleyMutagenesisOuabagenin (Pubchem CID: 262968)Ouabain (Pubchem CID: 439501)P-glycoproteinProscillaridin A (Pubchem CID: 16219784)Strophanthidin (Pubchem CID: 6185)Vesicular transport assay

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Drug Transport

Background:

  • Digitalis-like compounds (DLCs) treat heart failure but have narrow therapeutic indices.
  • Drug-drug interactions involving transporters like P-glycoprotein (P-gp) contribute to DLC toxicity.
  • P-gp's role in other DLCs' disposition beyond digoxin is largely unknown.

Purpose of the Study:

  • To investigate the transport of fourteen DLCs by human P-glycoprotein (P-gp).
  • To identify novel P-gp substrates among DLCs and understand their interaction mechanisms.

Main Methods:

  • Utilized membrane vesicles from human embryonic kidney (HEK293) cells overexpressing P-gp.
  • Quantified DLC transport using liquid chromatography-mass spectrometry (LC-MS).
  • Confirmed in vivo transport in rats and analyzed P-gp mutations.

Main Results:

  • Identified convallatoxin as a novel P-gp substrate with a Km of 1.1±0.2 mM.
  • Demonstrated in vivo P-gp-mediated transport of convallatoxin in rats, affecting brain and kidney concentrations.
  • Pinpointed Val982 as a critical amino acid for convallatoxin transport by P-gp.

Conclusions:

  • Convallatoxin is a new substrate for P-glycoprotein (P-gp).
  • The amino acid residue Val982 is crucial for convallatoxin transport by P-gp.
  • These findings enhance understanding of DLC interactions with P-gp, informing drug development and safety.