Biology Reference
In-Depth Information
parameters used in PBPK models (i.e., tissue partition coefficients) describe the relative
solubility of the chemical in various media (e.g., air, blood, and tissues). Biochemical
parameters include the rates of absorption, metabolism, macromolecular binding,
and excretion. One of the major drawbacks of developing PBPK models is the large
amount of physiological and biochemical data set requirements.
To develop a PBPK model, one must first consider which compartments of the
organism to include. The compartments may be specific organs, anatomical regions, or
lumped tissue groups, and their inclusion depends on which animal is being studied
and whether the compartment contributes to the uptake, disposition, and/or toxicity
of the chemical being modeled. For example, the lung, gastrointestinal tract, and skin
may be included because of their ability to serve as sites of absorption, and the kidneys
may be included because of their ability to serve as portals of excretion. Tissue parti-
tion coefficients and the metabolic capacity of a particular tissue also contribute to
chemical disposition. For example, fat is often included in PBPK models because of
the high partition coefficient of lipophilic chemicals (e.g., organochlorine pesticides)
in adipose tissue, and the liver is often included as a separate compartment because of
its involvement in the metabolism of a wide variety of chemicals. Tissues that are target
sites for toxicity are also often included in PBPK models.
The next step in PBPK model development is to write a mass balance equation for
each compartment to describe the rate of change of chemical concentration in that
compartment as a function of time. In the most general case, the mass balance equation
for each tissue compartment is:
Rateof change
=
(
Rateof uptake
)
(
Rateof removal
).
(61)
The rate of removal is the summation of removal by efflux back into the blood-
stream, metabolism within the tissue, and excretion (e.g., biliary excretion in the liver
or urinary excretion in the kidney). For simplicity, tissue compartments that have no
capacity for metabolism or excretion will be considered. In this case, the rate of change
of chemical concentration in the tissue is the difference in the rates of uptake and efflux.
For uptake to occur from blood into a particular tissue compartment, the free chemical
must diffuse out of the capillary space into the interstitial fluid and then diffuse across
the plasma membrane to enter the intracellular space ( Figure 6.12A ). It is assumed that
diffusion from the capillary membrane into the interstitial space is very rapid relative
to diffusion from the interstitial space into the intracellular space, and the vascular and
interstitial subcompartments are represented as one homogeneous subcompartment
referred to as the extracellular space ( Figure 6.12B ). Free chemical in the blood enters
the extracellular space of the tissue compartment at a rate (mass/time) that is the prod-
uct of blood flow to the tissue ( Q t , units of volume/time) and the concentration of the
free chemical in the arterial blood ( C a ). Diffusion of the chemical from the extracellular
space across the plasma membrane and into the intracellular space is governed by Fick's
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