Distribution and Pharmacokinetics Models - Pesticide Biotransformation and Disposition - page 118

site of action and ultimately protection from toxicity. The physiology of the organism
and the physicochemical characteristics of the pesticide are important factors in the
distribution of absorbed pesticides.
Total Body Water
Chemicals in the body move throughout the water compartments of the body. As
already discussed, the ability of chemicals to move between the various water compart-
ments is limited by the physicochemical properties of the chemical. Total body water
consists of plasma water, interstitial water, and intracellular water. In humans, approxi-
mately 60% of body weight is water, with plasma, intracellular, and interstitial water
accounting for 5, 15, and 40% of body weight, respectively. Plasma water, which repre-
sents approximately 53-58% of blood volume in humans, plays an essential role in the
distribution of absorbed chemicals.
For a chemical to move from blood (plasma water) into tissues, it must cross the
endothelial cell layer lining the capillaries (i.e., capillary wall) to enter the interstitial
water and then cross the plasma membrane to enter the intracellular water. Chemicals
exist in blood as free circulating chemicals or are noncovalently bound to plasma pro-
teins. The rates of association with and dissociation from plasma proteins are very rapid
(on the order of milliseconds), and it is assumed that the bound and free forms of
the chemical are in equilibrium. The capillary wall is permeable to small molecules,
but not readily permeable to high-molecular-weight molecules such as plasma pro-
teins. Only free chemicals that are small enough to pass through the capillaries, then,
are available to move from plasma water to interstitial water. The processes for crossing
plasma membranes described in Chapter 3 govern passage from the interstitial water to
the intracellular water.
Rate and Extent of Distribution
Factors that influence the rate and extent of distribution of a chemical to a particular
tissue include the blood flow to the tissue (rate of delivery), the mass of the tissue, the
ability of the chemical to cross membranes, and the affinity of the chemical for the
tissue relative to blood. The rate of distribution of a chemical from blood to tissues
can be perfusion- or diffusion-rate limited. For lipophilic chemicals that rapidly cross
membranes, the rate of delivery to tissues is limited by blood flow (perfusion-rate lim-
ited). For polar and ionized chemicals that do not readily cross the plasma membrane,
the rate of delivery to tissues is limited by diffusion (diffusion-rate limited). Plasma
protein binding increases the rate of distribution to tissues for toxicants that are not
diffusion-rate limited. The free toxicant may readily cross the capillary wall, effectively
decreasing its free concentration in blood. Bound toxicant then dissociates from plasma
proteins to maintain the equilibrium between the bound and the free forms, yet the
new free molecules rapidly leave the blood, which further increases the dissociation of