 Section 1  Pharmacokinetic Concepts 
Drugs are cleared primarily by the liver and kidneys. Excretion into the urine is a major route of elimination for metabolites and unchanged drug.
Most drugs are eliminated by a firstorder process. With firstorder elimination, the amount of drug eliminated is directly proportional to the serum drug concentration (SDC).
With first order elimination, at a certain point in therapy, the amount of drug administered during a dosing interval exactly replaces the amount of drug excreted. When this equilibrium occurs (rate in = rate out), steadystate is reached.
Clearance (CL)
Clearance is a descriptive term used to evaluate efficiency of drug removal
from the body. Clearance is not an indicator of how much drug is being removed;
it only represents the theoretical volume of blood which is totally cleared of drug
per unit time. Because clearance is a firstorder process, the amount of
drug removed depends on the concentration.
Clearance can be thought of as the proportionality constant that makes the average steadystate drug level equal to the rate of drug administration. Clearance (rate out) can be calculated from the dose (rate in) and average steadystate concentration:
Elimination rate constant (Kel)
With firstorder elimination, the rate of elimination is directly proportional to
the serum drug concentration (SDC). There is a linear relationship between rate of
elimination and SDC. Although the amount of drug eliminated in a firstorder
process changes with concentration, the fraction of a drug eliminated remains
constant. The elimination rate constant (Kel) represents the fraction
of drug eliminated per unit of time.
Here is an example of a first order process:
Time
(hrs)
Amount remaining
in body
Amount
eliminated
Fraction
eliminated
0
1000


1
850
150
0.15
2
723
127
0.15
3
614
109
0.15
4
522
92
0.15
5
444
78
0.15
The serum level curve observed from a drug eliminated by a first order process:
A plot of this same data using a log scale on the yaxis results in a straight line.
The slope of this straight line correlates to Kel.
Mathematically, this relationship may be represented by the following equation. If we plug in postdistribution serum levels (i.e., peak and trough levels), and the time difference between them, we can calculate a Kel which is specific for this patient:
Once we have the Kel, we can rearrange this equation to predict the time it takes to reach a specific serum level. If we plug our target peak and trough levels in, then we can use this equation to calculate an ideal dosing interval (tau):
Halflife (t ½)
Another important parameter that relates to the rate of drug elimination is halflife (t ½).
The halflife is the time necessary for the concentration of drug in the plasma to decrease by half.
Both t ½ and Kel attempt to express the same idea, how quickly a drug is removed, and therefore,
how often a dose has to be administered. An important relationship between t ½ and Kel can be
shown by mathematical manipulation:
Relationship between Kel, Vd, and CL
Kel (and t ½) are dependent upon clearance and the volume of distribution.
However, it is invalid to make any assumptions about the Vd or CL of
a drug based solely upon knowledge of its halflife.
Summary
 Section 1  Pharmacokinetic Concepts 