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Related Concept Videos

Physiological Pharmacokinetic Models: Assumption with Protein Binding01:13

Physiological Pharmacokinetic Models: Assumption with Protein Binding

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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...
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Drug Distribution: Plasma Protein Binding01:29

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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...
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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.
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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.
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The apparent volume of distribution (Vd) is a crucial pharmacokinetic parameter representing the hypothetical body fluid volume into which a drug disperses. It is calculated based on the total amount of drug in the body (estimated from the administered dose and bioavailability) divided by the plasma drug concentration. The total amount of drug in the body does not directly refer to the dose given but is derived by accounting for absorption, distribution, metabolism, and excretion processes.
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A loading dose is an essential pharmacological strategy to rapidly achieve the target plasma drug concentration necessary for an immediate therapeutic effect. This approach is especially critical for drugs characterized by slow absorption or extended half-lives, where delaying therapeutic plasma levels could compromise treatment outcomes. By administering a loading dose, clinicians ensure a prompt onset of drug action, even for agents with complex pharmacokinetic profiles.Achieving steady-state...
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Visualization of plasma and tissue binding using dose fractions parameter.

Andreas Svennebring1

  • 1Department of Pharmaceutical Biosciences, Division of Pharmaceutical Bioinformatics, Biomedical Centre, Uppsala University, Uppsala, SE 751 24, Sweden.

Drug Development Research
|October 16, 2014
PubMed
Summary

Introducing dose fractions to visualize drug pharmacokinetics. This concept offers precise terminology for drug distribution, enhancing understanding of drug exposure and binding states.

Keywords:
dispositiondistributiondose fractionin vitro/in vivo correlationsprotein binding

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Area of Science:

  • Pharmacokinetics and Drug Metabolism
  • Medicinal Chemistry
  • Quantitative Pharmacology

Background:

  • Current understanding of drug distribution often focuses on plasma-free fraction, with less emphasis on tissue binding.
  • High plasma protein binding (>95%) can lead to skepticism regarding drug safety and efficacy.
  • The Øie-Tozer model provides a framework for understanding drug distribution across different compartments.

Purpose of the Study:

  • To introduce and define the concept of "dose fractions" for visualizing drug pharmacokinetics.
  • To propose "free dose fraction" as a valuable term for discussing drug exposure.
  • To suggest "plasma protein bound dose fraction" as a metric for assessing risks associated with protein binding variations.

Main Methods:

  • Utilizing the Øie-Tozer model to analyze the distribution of total bioavailable drug dose.
  • Defining and calculating novel dose fractions based on location and binding states.
  • Applying these concepts to re-evaluate the implications of high plasma protein binding.

Main Results:

  • The concept of dose fractions offers a more precise way to describe drug distribution and binding.
  • The "free dose fraction" term can enhance discussions on drug exposure.
  • The "plasma protein bound dose fraction" provides a quantifiable measure of risk related to protein binding fluctuations.

Conclusions:

  • Dose fractions provide a novel and valuable framework for understanding drug pharmacokinetics and distribution.
  • The proposed terminology enhances precision in medicinal chemistry and pharmacology.
  • This approach may help to re-evaluate the clinical significance of high plasma protein binding.