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Physiological pharmacokinetic models, often called flow-limited or perfusion models, typically assume a swift drug distribution between tissue and venous blood, creating a rapid drug equilibrium. This premise is based on the idea that drug diffusion is extremely fast, and the cell membrane presents no barrier to drug permeation. In this scenario, where no drug binding occurs, the drug concentration in the tissue equals that of the venous blood leaving the tissue. This greatly simplifies the...
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Area of Science:

  • Biochemistry
  • Cell Biology
  • Physical Chemistry

Background:

  • Biochemical reactions in cells depend on diffusive search within crowded cytoplasm.
  • Cytoplasmic rearrangements create dynamic spatiotemporal heterogeneities, altering local diffusion and first-passage time distributions.

Purpose of the Study:

  • To investigate the impact of dynamic spatiotemporal heterogeneities on diffusion-limited reactions.
  • To develop a mathematical framework for analyzing diffusion in heterogeneous cellular environments.

Main Methods:

  • Derivation of the probability density function for first-passage time under heterogeneous diffusion.
  • Mathematical modeling of Brownian motion in dynamic, overcrowded media.

Main Results:

  • Dynamic disorder broadens the first-passage time distribution for diffusion-limited reactions.
  • Heterogeneous diffusion increases the likelihood of both short and long trajectories to reactive targets.
  • On average, disorder slows reaction kinetics, but individual search events are accelerated.

Conclusions:

  • Dynamic spatiotemporal heterogeneities significantly influence cellular reaction dynamics.
  • The developed framework allows translation of homogeneous diffusion results to heterogeneous systems.
  • Despite slowing overall kinetics, dynamic disorder enhances the efficiency of individual molecular searches.