Distribution and Pharmacokinetics Models - Pesticide Biotransformation and Disposition - page 119

bound toxicant, and so on. In contrast, distribution of more polar compounds that are
diffusion-rate limited is dependent on the extent of protein binding.
Initial distribution is influenced primarily by blood flow to tissues, whereas final
distribution is influenced primarily by the affinity of the chemical for various tissues
relative to blood (i.e., the tissue partition coefficient). In the early phase of distribu-
tion, tissues that receive a high blood flow (e.g., liver, kidney, and brain) may achieve
high concentrations of the chemical even though the tissue partition coefficient for
that chemical is low. Likewise, tissues that are slowly perfused (e.g., adipose) may
achieve a low concentration of the chemical in the early phase of distribution even
though the tissue partition coefficient for that chemical is very high. Later in the dis-
tribution phase, however, the chemical redistributes to tissues based on tissue partition
coefficients, and the chemical is more concentrated in tissues with relatively high par-
tition coefficients. Pesticides and other xenobiotics do not have the same tissue parti-
tion coefficient for all tissues. For example, dimethoate has a relatively high affinity for
liver, muscle, and brain ( Garcia-Repetto et al., 1995 ), whereas the chlorinated insecti-
cides DDT, aldrin, and dieldrin are lipophilic and have high affinities for adipose tissue
( Lehman, 1956; Robinson et al., 1969 ).

Volume of Distribution
When a chemical is absorbed and distribution is complete, its concentration in blood
depends on the amount absorbed and the extent of tissue distribution. The apparent
volume of distribution ( V d ) is a proportionality constant that relates the amount of
chemical in the body to its concentration in plasma,

Amount in body
Concentration in plasma

( )

V d

=

) ,

(1)

(

where V d is the theoretical volume of fluid the chemical would occupy to achieve the
observed concentration in plasma and does not necessarily correspond to the volume
of a particular body fluid compartment. For example, a chemical that is sequestered in
a particular tissue will have a low concentration in plasma and a corresponding high
volume of distribution, which may in fact be greater than the total body water. The V d
is often normalized by body weight, so the total body water is often quoted as 0.6 L/
kg, and some chemicals whose distribution is greater than this physiological value are
often very lipophilic chemicals or weak bases as they have a greater affinity for tissues
than for plasma proteins. As only the plasma concentration and not the tissue concen-
trations for these chemicals can be measured in humans, a large volume of distribution
is computed based on the known small plasma concentration and known amount in
the body. Many of the pesticides are lipophilic substances and fall into this category of
chemical with large volumes of distribution. However, chemicals that are large mac-
romolecules and/or weak acids that bind to plasma proteins are less likely to display