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Related Concept Videos

Drug Distribution: Tissue Binding01:21

Drug Distribution: Tissue Binding

3.8K
Upon entering the systemic circulation, drugs can distribute into the interstitial and intracellular fluid of various tissue cells. This distribution is facilitated by the binding of drugs to different cellular components within tissues, which may lead to drug accumulation in specific areas. Drugs bound to tissue components serve as reservoirs that release free drugs back into the system, prolonging the drug's overall action. However, this accumulation can also result in local toxicity.
For...
3.8K
Tissue-Drug Binding: Localization of Drugs and its Significance01:24

Tissue-Drug Binding: Localization of Drugs and its Significance

365
Body tissues, comprising approximately 40% of the body weight, are crucial in drug distribution and localization. These tissues can serve as drug storage sites, competing with plasma binding sites for drug molecules.
Drugs can bind to different tissue components, enhancing their distribution and localization. The factors influencing drug localization in tissues include the drug's lipophilicity, structural characteristics, tissue perfusion rate, and pH differences. These factors determine...
365
Factors Affecting Drug Distribution: Tissue Permeability01:30

Factors Affecting Drug Distribution: Tissue Permeability

561
The drug distribution process within the human body is a complex interplay of various physicochemical properties inherent to the drugs. These properties, including molecular size, ionization degree, partition coefficient, and stereochemical nature, significantly impact how drugs permeate biological membranes to reach their target tissues.
Small molecules with a molecular weight below 500 to 600 Daltons can easily pass through the capillary membrane, gaining access to different tissues. Larger...
561
Drug Distribution: Plasma Protein Binding01:29

Drug Distribution: Plasma Protein Binding

8.1K
Drugs predominantly attach to plasma proteins, with only a small percentage remaining unbound. The unbound portion can be calculated as one minus the bound fraction. Acidic drugs form large, inactive complexes by reversibly binding to plasma albumin, which prevents them from diffusing across biological barriers. These drug-protein complexes act as reservoirs for the drugs. As the concentration of unbound drugs decreases, these complexes quickly dissociate to release the free drug, maintaining...
8.1K
Physiological Pharmacokinetic Models: Assumption with Protein Binding01:13

Physiological Pharmacokinetic Models: Assumption with Protein Binding

187
Physiological models with protein binding in pharmacokinetics offer a sophisticated approach to understanding drug disposition. These models consider drug-protein interactions, enabling them to effectively predict drug concentrations in different organs and tissues. This precision aids in accurate drug dosing, providing a significant advantage over conventional models. A key process within these models is equilibration, which ensures that drug concentrations achieve a steady state within the...
187
Drug Distribution: Overview01:11

Drug Distribution: Overview

634
Drug distribution within the body is a dynamic process involving the movement of a drug in two directions across various compartments: from the bloodstream into tissues (tissue uptake) and from tissues back into the bloodstream (tissue release or redistribution). This process is passive and primarily driven by two variables: the concentration gradient between the bloodstream and the extravascular tissues and the drug's ability to cross the cell membrane.
Initially, the free drug in the...
634

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Spatial Measurements of Perfusion, Interstitial Fluid Pressure and Liposomes Accumulation in Solid Tumors
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Spatial Measurements of Perfusion, Interstitial Fluid Pressure and Liposomes Accumulation in Solid Tumors

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Structural attributes influencing unbound tissue distribution.

Christine C Orozco1, Karen Atkinson1, Sangwoo Ryu1

  • 1Medicine Design, Pfizer Worldwide Research & Development, Groton, CT, USA.

European Journal of Medicinal Chemistry
|November 17, 2019
PubMed
Summary
This summary is machine-generated.

This study measured unbound tissue-to-plasma partition coefficients (Kpuu) for 56 compounds in rats. Drug distribution varied by tissue, with liver showing the highest enrichment and brain the lowest, offering insights for drug design.

Keywords:
BrainDispositionDrug designFraction unboundHeartK(puu)LiverMetabolismPharmacokineticsSkeletal muscleTissue unbound partition coefficientTransportersWhite adipose

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Area of Science:

  • Pharmacokinetics and Drug Metabolism
  • Physiologically Based Pharmacokinetic Modeling
  • Drug Discovery and Development

Background:

  • Understanding drug distribution in tissues is crucial for optimizing therapeutic efficacy and minimizing toxicity.
  • Tissue-to-plasma partition coefficients (Kpuu) quantify unbound drug concentrations in tissues relative to plasma.
  • Variability in drug distribution necessitates investigation into factors influencing tissue uptake and retention.

Purpose of the Study:

  • To determine unbound tissue-to-plasma partition coefficients (Kpuu) for a diverse set of compounds in multiple rat tissues.
  • To establish the rank order of tissue enrichment and identify tissues with selective drug distribution.
  • To identify physicochemical attributes that predict drug distribution patterns for rational drug design.

Main Methods:

  • Intravenous infusion of 56 structurally diverse compounds in rats.
  • Measurement of unbound tissue-to-plasma partition coefficients (Kpuu) in white adipose, brain, heart, liver, and skeletal muscle.
  • Application of recursive partitioning to identify physicochemical drivers of tissue distribution.

Main Results:

  • Rank ordering of median Kpuu values: liver (4.5) > heart (1.8) > adipose (1.2) > skeletal muscle (0.6) > brain (0.05).
  • Liver exhibited the highest drug enrichment, while the brain showed the most significant impairment.
  • Acids and zwitterions generally had lower Kpuu values than bases and neutrals across most tissues, except the liver.
  • Selective tissue distribution was observed, influenced by compound chemotype.

Conclusions:

  • Compound chemotype significantly influences tissue distribution, enabling targeted or restricted drug exposure.
  • Identified physicochemical attributes provide valuable design principles for achieving asymmetric tissue distribution.
  • This research offers insights for optimizing drug efficacy and reducing toxicity through rational drug design.