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Related Concept Videos

Nonlinear Pharmacokinetics: Bioavailability and Protein-Drug Binding01:22

Nonlinear Pharmacokinetics: Bioavailability and Protein-Drug Binding

631
When a drug follows nonlinear pharmacokinetics, its bioavailability, the amount of the drug that reaches the systemic circulation, can change with different doses. This is due to the presence of a saturable pathway. The pathway becomes saturated as the drug concentration increases, decreasing the absorption rate. Consequently, the drug's bioavailability may be lower than expected at higher doses.
To quantify the extent of bioavailability, pharmacologists often use a parameter called .
631
Nonlinear Pharmacokinetics: Causes of Nonlinearity01:22

Nonlinear Pharmacokinetics: Causes of Nonlinearity

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Nonlinearity in drug pharmacokinetics is caused by various factors influencing how a drug is absorbed, distributed, metabolized, and excreted. Understanding these nonlinear processes is crucial for predicting drug behavior in the body and optimizing drug dosing regimens.
Nonlinear drug absorption can occur when the process is rate-limited by solubility, carrier-mediated transport systems, or saturation of the presystemic gut wall or hepatic metabolism. For instance, high doses of riboflavin...
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Factors Affecting Protein-Drug Binding: Protein-Related Factors01:20

Factors Affecting Protein-Drug Binding: Protein-Related Factors

576
Drug binding to proteins is a key aspect of pharmacokinetics and can influence a drug's distribution, absorption, and elimination in the body. Several factors, including the drug's physiochemical properties, protein concentration, disease states, and the number of binding sites on the protein, influence this process.
The physicochemical properties of a drug play a significant role in its ability to bind to proteins. Lipophilic drugs, which dissolve in fats, oils, and lipids, can be...
576
The Equilibrium Binding Constant and Binding Strength02:18

The Equilibrium Binding Constant and Binding Strength

15.2K
The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:
15.2K
Drug Distribution: Plasma Protein Binding01:29

Drug Distribution: Plasma Protein Binding

9.0K
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...
9.0K
Protein-Drug Binding: Determination Methods01:22

Protein-Drug Binding: Determination Methods

676
Determining protein-drug binding can be achieved through indirect and direct methods, each providing valuable insights into the interaction between proteins and drugs.
Indirect methods involve isolating the bound drug from its free form in biological samples such as blood, serum, or plasma. These techniques aim to measure the percentage of drugs bound to proteins. Equilibrium dialysis is a commonly used method where the free drug concentration at equilibrium is measured by separating the bound...
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Pull-down of Calmodulin-binding Proteins
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Nonlinear Protein Binding: Not What You Think.

Amelia N Deitchman1, Ravi Shankar Prasad Singh2, Hartmut Derendorf1

  • 1Department of Pharmaceutics, University of Florida, Gainesville, Florida 32610.

Journal of Pharmaceutical Sciences
|April 8, 2018
PubMed
Summary
This summary is machine-generated.

Atypical nonlinear protein binding, where unbound drug fraction decreases with higher concentrations, can overestimate drug exposure. This phenomenon, exemplified by tigecycline, necessitates re-evaluation of clinical pharmacokinetics and efficacy.

Keywords:
clinical pharmacokineticsnonlinear pharmacokineticsprotein binding

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Area of Science:

  • Pharmacology
  • Biochemistry
  • Drug Metabolism

Background:

  • Nonlinear protein binding traditionally assumes increased unbound drug fraction with higher total drug concentration.
  • Recent studies on tetracyclines, including tigecycline, reveal counterintuitive nonlinear binding where unbound fraction decreases at higher concentrations.
  • The role of calcium chelation in tigecycline-protein interactions is noted, but clinical implications remain underexplored.

Purpose of the Study:

  • To define typical and atypical nonlinear protein binding.
  • To explore the theoretical pharmacokinetic implications of nonlinear protein binding.
  • To investigate the clinical relevance of atypical nonlinear protein binding using tigecycline as a model.

Main Methods:

  • Overview of protein binding theory.
  • In silico simulations and calculations.
  • Analysis of tigecycline as an example of atypical nonlinear binding.

Main Results:

  • Atypical nonlinear protein binding can lead to overestimation of free drug exposure and tissue penetration when not accounted for.
  • Simulations demonstrate the impact of nonlinear binding on pharmacokinetic parameters.
  • The study highlights the importance of considering nonlinear binding for accurate drug assessment.

Conclusions:

  • Nonlinear protein binding significantly impacts pharmacokinetic and pharmacodynamic assessments.
  • Failure to account for atypical nonlinear binding may lead to inaccurate predictions of drug efficacy.
  • Understanding this phenomenon is crucial for potential clinical dose adjustments and developing novel therapeutic strategies.