Distribution and Pharmacokinetics Models - Pesticide Biotransformation and Disposition - page 120

extravascular distribution, that is, move from the plasma into tissues. Such chemicals are
described as having small volumes of distribution and their V d values are less than the
normal physiological volume described above (0.6 L/kg) and are closer to the plasma
volume of 3 L (0.05 L/kg) or the albumen volume (7.5 L or 0.1 L/kg), suggesting that
the chemical after absorption was restricted to the plasma compartment because of its
large molecular size and/or by noncovalent binding to albumin. The herbicide 2,4-D
is a good example of a weak organic chemical that binds to plasma proteins and has a
low volume of distribution (0.27 L/kg) in humans ( Timchalk, 2004 ).
There are different ways to calculate V d and these derived values have different inter-
pretations and applications. For example, when computing how much chemical is in the
body from a plasma concentration one needs to consider whether the state of drug dis-
tribution is, at time 0, under equilibrium conditions, or at a pseudo-equilibrium state of
distribution ( Toutain and Bousquet-Melou, 2004a ). The apparent volume of the central
compartment, V c , is for intravenous (iv) doses only and is calculated as follows:

D
C n

V

c =

(2)

,

∑

where D is the dose and C n are the intercepts of the various phases of chemical dis-
position obtained by fitting the concentration-time profile. V c is the initial volume of
distribution and it is related to the amount in the body (i.e., the dose, D ) before the
chemical is distributed or eliminated. If distribution is instantaneous, then the body can
be reduced to one homogeneous compartment and V c remains the V d . However, there
are many substances for which there is a non-instantaneous distribution, and there is a
distribution phase during which the chemical partitions into various tissues, and the
decline in plasma concentration is not due to elimination but to this partitioning pro-
cess. This continues until pseudo-equilibrium of distribution is achieved, whereby the
net exchange between the central compartment and the tissue compartment is zero.
At this point further decline in plasma concentration is due to irreversible elimination
of the chemical from the body. It is during this terminal phase that a V d value known
as V area , which is greater than the initial V d (i.e., V c ), can be calculated; it takes into
account the amount of chemical in the body and the plasma concentration during this
phase. The apparent volume of distribution, V area , is based on trapezoid AUC  (area)
and elimination rate, λ z . This can apply to iv but also to oral exposure if complete
absorption ( F  1) is assumed and can be calculated as follows:

F D
AUC

V

area =

(3)

.

∞

The third V d value that may be reported is the apparent volume of distribution
under steady-state conditions, V ss . This can be estimated graphically from trapezoid
total area measurements and applies to an iv infusion dose or to situations in which the