Drug Pharmacokinetics

Following Oral Dosing

• KINITICS Of ABSORPTION
• The oral absorption of drugs
often approximates first-order
kinetics especially when given
in solution.
• The same holds true for the absorption of
drugs from many other extravascular sites
including subcutaneous tissue and
muscle.
• Under these circumstances absorption is
characterized by an absorption rate
constant ka and a corresponding half-life.
• The t1/2s for absorption of drugs
administered orally in solution or in
rapidly disintegrating forms usually
range from 15min to 1hr.
• The absorption sometimes is zero
order. The fig. below shows the shape
of the graphs of the two cases.
• FIRST-ORDER ABSORPTION
• A graphic procedure to test whether or
not absorption is a first-order process
and if so, to determine the absorption
half-life, is known as the method of
residuals.
• The procedure is as follows:
• (1) Back extrapolate the log linear
portion of the declining phase.
• Let C← denote the plasma
concentration along this
extrapolated line.
• (2) Subtract the observed plasma
concentration (C) from the
corresponding extrapolated value
at each time point.
• (These calculations are shown in
the table below).
• (3) Plot the residuals (C← - C )
against time on the same semilog
graph paper.
• If the residual plot is a straight line
then absorption is first-order
process.
• From the graph above: the absorption
t1/2 is 1.3hr. The corresponding
absorption rate constant ka is
0.693/1.3 = 0.53hr-1 .
• The absorption half-life, of many
drugs is 30 minute or less.
• To examine the underline basis of
the method of residuals:
• At any time the plasma
concentration following
extravascular administration is
given by:
For the equation1, 1

when plotted on a
semilog paper:
Y-intercept =
FDKa/V(ka-k)
And the slope of
the linear part
equals -k/2.303
• where C is the plasma concentration of
drug at any time t following the
administration of the dose, V is the
apparent volume of distribution, F is the
fraction of the orally administered dose
which is absorbed, and ka and K are the
apparent first-order absorption and
elimination rate constants, respectively.
• Assuming that (ka > k), the value of (ka .t)
is greater than (k .t), and hence e-ka.t
approaches zero more rapidly than does
e-k.t . At some time past the peak plasma
concentration, e-ka.t is essentially zero
(absorption is over) and the extrapolation
line is given by:
• Subtracting (C) from (C←) i.e . (C← - C ) or
equation (1) from equation (2) yields the
equation three below:
And taking natural logs gives the
equation four below:
• Hence , if absorption is a first-
order process a semilog plot of the
residual value against time is a
straight line with a slope of - ka.
When this residual line is not log
linear, absorption is not a simple
first-order process.
• Lag Time:
• This is the time between
administration and start of absorption.
• The lag time of drug absorption is
confirmed when the extrapolated line
and residuals line intersect at a point
after time zero.
• The time at the point of
intersection on the x-axis is the
lag time. It is different from the
onset of the drug effect, which
is the time required for the drug
to reach the MEC at the site of
action.
• Events at the Peak:
• The peak concentration Cmax and the time
of its occurrence tmax are often important
factors influencing drug therapy. These
two parameters together can give an
estimation for the speed of the drug
absorption for a given dose.
• The value of tmax is calculated as follows:
• At that time, rate of absorption is
matched by rate of elimination and
hence the rate of change of plasma
concentration is zero i.e. dC/dt = 0. So
to determine tmax we must determine
first dC/dt, which by differentiation of
equation1 (C = [(F . Dose . Ka)/V(ka-k)]
(e-k.t - e-ka.t ) given as :
• At tmax when dC/dt = 0 it follows from the
equation 5 that:

• NB: that if there is lag time tlag then Cmax occurs

after (tmax + tlag).
• Practice Problems
• 1. After oral administration of a single dose of
an antibiotic, the following concentrations were
measured:
Time hr 0 0.2 0.5 1.0 2.0 2.5 4.0 6.0 8.0

Drug conc 0 88 185 277 321 311 246 161 102

µg/mL

• Calculate the first order rate constant ka

• 2. The plasma drug concentration in a patient
who had received a single oral dose of a drug
(10mg/kg) was determined as follows:
Time 0 1 2 3 4 6 8 10 15 20 25 30
• hr
Drug 0 84 141 177 199 207 188 176 111 63 33.5 17.5
conc
µg/mL

• Plot the plasma conc time profile and find the

following parameters directly from the graph
• a. the elimination rate constant and the
elimination half-life b. The tmax c. The Cmax
• 3. Two drugs have the following
pharmacokinetic parameters after a single oral
dose of 500mg (both drugs are completely
absorbed):
Drug Ka (hr-1) K (hr-1) Vd (L)

A 1.0 0.2 10

B 0.2 1.0 20

• a. Calculate tmax for each drug

• b. Calculate Cmax for each drug
• 4.The plasma concentration time profile after a
single oral dose can be expressed as:
• Cp = [FDKa/Vd(Ka-K)](e-kt-e-kat)
• After administration of a single oral 500mg dose
of a drug, the plasma concentration time profile
can be expressed as:
• Cp = 75mg/L(e-0.1t-e-0.9t)
• a. Calculate the tmax
• b. Calculate the Cmax
• c. Calculate the same parameters if the dose is
100mg