Saturable Fractal Pharmacokinetics and Its Applications - Mathematical Methods and Models in Biomedicine - page 330

Fig. 2 Schematic illustration
of the drug distribution
processes

Time-dependent pharmacokinetics is present when the pharmacokinetic param-
eters vary with time due to actual physical alterations in the body, whether in
the form of physiological changes related to the body's circadian rhythms (called
chronopharmacokinetics) or chemically induced changes brought about by the
introduction of the drug into the body [ 38 ]. The potential causes of time-dependence
fall into the categories of absorption and elimination parameters, metabolism,
plasma binding, renal or hepatic clearance, overall systemic clearance, and enzyme
activity [ 38 ].
Both dose-dependence and time-dependence can be present in the same system
(i.e. the pharmacokinetic parameters describing a system can vary both in time and
with dose), and in fact, the sources proposed for both are similar. The causes of
dose-dependent pharmacokinetics may include oral absorption, tissue distribution,
protein binding in both the plasma and tissues, and elimination [ 40 ].
Of particular significance is the role of drug distribution processes throughout the
body which we briefly discuss below. Distribution processes are illustrated in Fig. 2
and they represent movement of drug molecules from the blood to and from the
tissues. Distribution is determined by: (a) partitioning across various membranes,
(b) binding to tissue components, (c) binding to blood components (RBC, plasma
protein), and (d) physiological volumes.
All of the fluid in the body, in which a drug can be dissolved, can be roughly
divided into three compartments:

1. Intravascular (blood plasma found within blood vessels): V = 3 L (4 % of body

weight)
2. Interstitial (fluid surrounding cells): V 9 L (13 % body weight)

3. Intracellular (fluid within cells, i.e. cytosol): V

=

= 28 L (41 % of body weight)

The distribution of a drug into these compartments is dictated by its physical and
chemical properties. Many drugs bind to plasma proteins in the blood stream and
plasma protein binding limits distribution. Consequently, a drug that binds plasma
protein diffuses less efficiently than a drug that does not.
To address the shortcomings of homogeneously stirred compartment models,
several mathematical formulations have been proposed. Liver clearance plays a