Drug distribution in the Body IV

Possible Modes of Drug Distribution
Following its uptake into the body, the
drug is distributed in the blood and
through it to the various tissues of the
body. Distribution may be restricted to
the extracellular space (plasma volume
plus interstitial space) or may also
extend into the intracellular space .
Certain drugs may bind strongly to tissue
structures, so that plasma concentrations
fall significantly even before
elimination has begun .
After being distributed in blood,
macromolecular substances remain
largely confined to the vascular space,
because their permeation through the
blood-tissue barrier, or endothelium, is
impeded, even where capillaries are
fenestrated. This property is exploited
therapeutically when loss of blood necessitates
refilling of the vascular bed,
e.g., by infusion of dextran solutions
. The vascular space is, moreover,
predominantly occupied by substances
bound with high affinity to plasma proteins
(determination of the plasma
volume with protein-bound dyes).
Unbound, free drug may leave the
bloodstream, albeit with varying ease,
because the blood-tissue barrier
is differently developed in different segments
of the vascular tree. These regional
differences are not illustrated in
the accompanying figures.
Distribution in the body is determined
by the ability to penetrate membranous
barriers . Hydrophilic
substances (e.g., inulin) are neither taken
up into cells nor bound to cell surface
structures and can, thus, be used to determine
the extracellular fluid volume
. Some lipophilic substances diffuse
through the cell membrane and, as a result,
achieve a uniform distribution .
Body weight may be broken down
as follows:
Further subdivisions are shown in
the table.
The volume ratio interstitial: intracellular
water varies with age and body
weight. On a percentage basis, interstitial
fluid volume is large in premature or
normal neonates (up to 50 % of body
water), and smaller in the obese and the
aged.
The concentration (c) of a solution
corresponds to the amount (D) of substance
dissolved in a volume (V); thus, c
= D/V. If the dose of drug (D) and its
plasma concentration (c) are known, a
volume of distribution (V) can be calculated
from V = D/c. However, this represents
an apparent volume of distribution
(Vapp), because an even distribution
in the body is assumed in its calculation.
Homogeneous distribution will not occur
if drugs are bound to cell membranes
or to membranes of intracellular
organelles or are stored within
the latter . In these cases, Vapp can exceed
the actual size of the available fluid
volume. The significance of Vapp as a
pharmacokinetic parameter is discussed