Biomedical Engineering Reference
In-Depth Information
terminology used is total clearance (
Q
cl
), which is the volume of plasma completely
cleared of a drug per unit time by all routes of the mechanism. Two major routes of
clearance mechanisms are excretion (for example, in the kidney) and metabolism
(for example, in the liver). If the intrinsic capacity of an organ to clear a drug is
high and exceeds plasma flow to that organ, then the clearance equals plasma flow
and is altered by changes in plasma flow.
Renal clearance
(or glomerular filtration)
is an excretory route for nonvolatile drugs and metabolites. Renal clearance (
Q
RC
)
is the volume of plasma completely cleared of the drug per unit time and given by
excretion rate in urine [mass/time]
Q
[volume/time]
=
(10.9)
RC
plasma concentration [mass/volume]
A method to determine
Q
RC
of a drug is to measure the drug excreted in the
urine between a time interval. In the midpoint of this time interval, concentration
of the drug is determined. Mechanism of renal excretion is inferred by comparison
of
Q
RC
to that of an indicator of glomerular filtration (creatinine). For example,
normal tubular secretion in a 70-kg person is 120 mL/min and less than that in-
dicates net reabsorption in the absence of plasma binding. However, a number
of factors such as extent of plasma binding, renal disease (creatinine clearance or
its estimate from serum creatinine provides a useful clinical indicator of impaired
renal function and is proportional to drug renal clearance), and urinary pH (reab-
sorption of drug with ionizable group is dependent on urinary pH; raising the pH
promotes excretion of acids, impairs excretion of bases) affect drug distribution.
Equation (10.9) is also useful to determine values experimentally for other terminal
regions such as bile, or exhaled air in which the amount of therapeutic agent is as-
sessed and correlated to the drug concentration in the plasma.
Substituting the new definitions of
V
D
and
Q
cl
into (10.5), plasma half-life of
a therapeutic agent is obtained as
V
ln 2
t
=
D
(10.10)
1/2
Q
cl
Hence, the plasma half-life is directly proportional to the apparent volume
distribution and inversely proportional to total clearance. For a given volume of
distribution, shorter half-lives are expected for higher clearance rates. For practi-
cal purposes of designing various therapeutic agents,
t
1/2
is used as an indicator to
understand the total clearance and volume of distribution.
EXAMPLE 10.1
A company has developed a contrast agent useful in magnetic resonance imaging. When
500 mg of the agent is administered, blood concentration is determined to be 31.25
mg/L. Within 30 minutes the concentration decreased to half the initial value. Calculate
the apparent volume of distribution and the clearance rate of the contrast agent.
