Drugs must get to their site of action to be useful, and in most
cases, we administer drugs at sites other than the site of
action. Understanding how drugs get to their site of action
and how long they stay there is essential to making therapeutic
decisions about which drug, what route, how much, how often, and
for how long.
Classically, how drug moves through the body can be described
with ADME, absorption, distribution, metabolism, and
elimination. We will highlight the clinically important
aspects of each stage of drug movement, as well as demonstrating
the effect that differences in these parameters make in drug
Remember that we most commonly measure the concentrations of
drug in the plasma or serum, even though many of our target cells
for drug activity are outside the plasma. This is based on
the assumption that plasma concentrations correlate with tissue
concentrations, so conclusions about tissue concentration can be
made from plasma concentrations. This may not be true for all
drugs, but it holds true for enough important compounds that it is
a reasonable assumption until proven otherwise.
Simulated graphs are presented below to demonstrate the effects
of changes in pharmacokinetic parameters. These simulations
were performed, at
the website of David Bourne.
Absorption is usually defined as the proportion of drug moving
from the administered drug product into the bloodstream.
Drugs administered IV are assumed to be 100% absorbed by
definition. For drugs administered PO, major losses of drug
occur by not crossing enterocyte membranes in the GI tract, via
metabolism in the gut wall (e.g., peptidases), and via metabolism
in the liver (since drug absorbed from the GI tract enters portal
circulation first and can therefore bring drug into contact with
enzymes in hepatocytes before it enters peripheral circulation).
Absorption rate can be indicated by the half-life of
absorption, sometimes designated as t1/2α.
A simulation of serum concentrations is presented in the graph
below, in which the only difference between the two lines is a
doubling of the absorption rate. This results in a higher
Cmax, as well as a shorter time above any given concentration (once
absorption is mostly completed).
Distribution refers to the movement of drug from the bloodstream
into the interstitial fluid and into other tissues. The
mathematical parameter usually used to describe distribution is the
volume of distribution (V or Vd or VDss). The volume of
distribution can be defined as the apparent volume of fluid needed
to contain the total amount of a drug in the body at the same
concentration as it is in the plasma. It is an indication of
whether drug tends to remain in the vascular system, in total body
water, or in tissues.
A simulation of serum concentration is shown below, in which the
only difference between the two lines is a doubling of the volume
of distribution. In this case, a higher volume of
distribution results in a lower peak concentration and lower
concentrations throughout the time course.
Metabolism may change pro-drug to active drug, active drug to
active metabolite, or active drug to inactive metabolite. A
basic understanding of how a drug is metabolized (or if a drug is
metabolized) will aid in clinical decision-making in cases in which
mechanisms of metabolism are compromised because of disease.
Active metabolites should also be considered when examining drug
concentration data, since graphs of concentration data may be
misleading if they do not contain parent drug and active
Elimination generally refers to elimination from plasma or
serum, and the rate of elimination is designated as ka.
Elimination half-life is the time taken for the serum concentration
to drop by half, and is often designated as t1/2β. For the
most part, it is assumed that the drugs we use regularly for
therapeutic purposes follow first order elimination. This
means that a constant proportion of drug is removed from the body
per unit time. There are some exceptions, in which a constant
amount of drug is removed from the body per unit time, designated
zero order. Zero order elimination generally occurs when
clearance mechanisms have become saturated, so zero order kinetics
are more often - Seen with toxic doses of drug.
A simulation of serum concentrations in which the elimination
rate is doubled is presented below. When elimination rate is
increased, overall concentrations are lower as is the peak
A simulation of serum concentrations is presented below, in
which the only difference between the lines is a doubling of the
dose administered. Careful examination of the graph reveals
that the peak concentration in the curve representing the doubled
dose is twice that of the lower dose, and the time that
concentrations remain above a particular level are moved over one
half-life (in this case half-life was set at 1.7 hours).
To be complete, we should briefly discuss how
pharmacokineticists generate mathematical descriptions of drug
movement to allow for predictions and to explain drug behavior and
clinical effects. The major methods of mathematical modeling
of drug concentration data include compartmental and
non-compartment modeling. Compartmental modeling is used to
mathematically describe drug movement under particular assumptions
about how drugs act; the compartments assumed are not anatomical
compartments but rather are artificial methods to describe rates of
drug movement. Non-compartmental modeling is based on
statistical moment theory, which makes no assumption about how
drugs move but rather assumes the drug concentrations at a given
time point are independent and can therefore be modeled in a
stochastic manner. Regardless of how modeling and
mathematically descriptions are performed, the goal is to explain
why drug is moving in a particular way and to make predictions
about drug movement.
Brunton, LL, Lazo, JS, and Parker, KL, Goodman & Gilman's
The Pharmacological Basis of Therapeutics, 11th edition,