Concepts
In most cases, we administer drugs at a different site than we want to drug to act. 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.
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 demonstrated to be untrue for a particular
compound.
Simulated graphs are presented below to demonstrate the effects of changes that impact drug movement. These simulations were
performed at the website of David Bourne, http://www.boomer.org/c/php/pk1701.php.
Absorption
Absorption is sometimes 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
at 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 t½.
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
Distribution refers to the movement of drug from the bloodstream into the interstitial fluid and 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
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
metabolite.
