When the rate of drug absorption falls below the rate
of drug elimination, the drug concentration begins to
fall. Eventually drug uptake ceases and the drug
concentrations depend only upon drug redistribution
and elimination. This phase is sometimes called the
post-absorptive phase.
The extent of uptake of a drug administered
extravascularly is limited by presystemic drug elimi-
nation. For oral dosing, this means metabolism by
intestinal cells and by hepatocytes during the trans-
hepatic passage of the portal blood carrying the
absorbed drug, the so-called first-pass effect. The
completeness of gastrointestinal uptake is quantified
by the parameter bioavailability. The bioavailable
fraction, F, is defined as the fraction of a drug dose
that reaches the systemic circulation after admini-
stration by an extravascular route.
Clearance
Elimination is the irreversible removal of drug
from the body by excretion or metabolism. Usually,
the rate of elimination is proportional to the amount
of drug in the plasma and rapidly accessible sites.
The constant of proportionality for this first-order
kinetic relationship is the elimination rate constant,
k
el
. Defining elimination in this form is not very
useful because the amount of drug is not measurable.
What is measurable is plasma drug concentration, so
what is needed is the relationship between the elimi-
nation rate and the drug concentration. That
relationship is
drug elimination rate
=
Cl C
(
t
)
where Cl is the systemic clearance rate, the constant
of proportionality for the relationship.
The irreversible removal of drug from the blood
perfusing an organ is called organ clearance and is
quantified as organ clearance rate. Just as the
systemic clearance rate is the constant of proportion-
ality between plasma drug concentration and the total
drug elimination rate, organ clearance rate, Cl
organ
, is
the constant of proportionality between plasma drug
concentration and the rate of drug elimination by the
organ,
drug elimination rate in organ
=
Cl
organ
C
(
t
)
Because total drug elimination is the sum of the
individual organ, or tissue, rates of drug elimination,
the systemic clearance rate is the sum of the organ
clearance rates. This makes it easy to calculate the
change in systemic clearance rate that attends a
change in one or more organ clearance rate. This is
extremely useful when adjusting drug dosages in the
setting of dysfunction of an eliminating organ.
Another way to express the clearance of drug by
an organ is the extraction fraction. The extraction
fraction, E
organ
, is the fraction of drug entering the
organ that is removed in one pass through the organ.
This fraction equals the drug elimination rate divided
by the drug delivery rate,
E
organ
=
drug elimination rate in organ
drug delivery rate to organ
Because the drug delivery rate is the product of the
organ plasma flow rate, Q
organ
, and the plasma drug
concentration, the extraction fraction can also be
calculated as,
E
organ
=
Cl
organ
Q
organ
Organ clearance.
Two organs, the kidneys and
the liver, are responsible for the elimination of most
drugs. The elimination of drugs by the liver is
accomplished by reversible uptake of drug by the
hepatocytes followed by metabolic inactivation of the
drug or excretion of unmetabolized drug in the bile.
The latter process is a route of elimination only if
there is minimal reabsorption of the drug (i.e., if
there is little enterohepatic recirculation of drug).
Over the usual pharmacologic ranges of plasma
concentrations, the hepatic uptake and metabolism of
most drugs show first-order kinetics, meaning that
the rate of elimination of the drug is proportional to
the concentration of the drug in the plasma.
Enzyme-catalyzed hepatic metabolism is saturable,
however, meaning that, at higher drug concentra-
tions, the rate of metabolism is less than propor-
tional to the concentration and, at very high concen-
trations, the rate of metabolism is constant.
The elimination of drugs by the kidney is accom-
plished by glomerular filtration and tubular
secretion. These processes are opposed by passive
back diffusion and tubular reabsorption. Approxi-
mately 20 percent of the plasma entering the
glomerulus is ultrafiltered. The ultrafiltrate consists
of water and low molecular weight solutes including
smaller proteins; larger proteins are excluded by
normal glomeruli. Nearly all of the water is
reabsorbed, resulting in high tubular urine drug con-
centrations. This generates a considerable urine-to-
plasma concentration gradient that causes passive
back diffusion of drug into the plasma. The degree
Drug Therapy
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