Advances in Biopharmaceutics and

Pharmacokinetics

Dr. Muzaffar Abbas

Practice Problems
1. Find the log of 35.
Enter the number 35 into your calculator.
Press the LOG function key.
Answer = 1.5441
(For some calculators, the LOG function key is
pressed first, followed by the number; the answer is
obtained by pressing the = key).
Notice that the correct answer for log 35 is the same
as calculating the exponent of 10, which will equal
35 as shown below.
Estimation—Since the number 35 is between 10 and
100 (ie, 101 and 102), then the log of 35 must be
between 1.0 and 2.0.
2. Find the log of 0.028
Estimation—Since the number 0.028 is between 10 -1
and 10-2, then the log of 0.028 must be between –1.0
and –2.0.
Solution
Use the same procedure above.
Enter the number 0.028 into your calculator.
Press the LOG function key.
Answer = –1.553
3. Find the antilog of 0.028.
The process for finding an antilog is the reverse of
finding a log. The antilog is the number that
corresponds to the logarithm, such that the antilog for
3 (in base 10) is 1000 (or 10 3). This problem is the
inverse of Practice Problem 2, above. In this case, the
calculation determines what the number is when 10 is
raised to 0.028 (ie, 100.028).
Solution
The following methods may be used, depending on
the type of calculator being used.
Method 1
If your calculator has a function key marked 10 x,
then do the following:
Enter 0.028.
Press 10x
Answer = 1.0666
4. Find the value of k in the following expression:
25 = 50e-4K
Solution

Take the natural logarithm, ln, for both sides of the

equation:

From Equation 2.5, ln e-x = –x. Therefore, ln e-4k= –4k

and ln 0.50 = –0.693.
(Calculator: Enter 0.5, then press LN function key.)
Graphs
The construction of a curve or straight line by
plotting observed or experimental data on a graph is
an important method of visualizing relationships
between variables.
By general custom, the values of the independent
variable (x) are placed on the horizontal line in a
plane, or on the abscissa (x axis), whereas the values
of the dependent variable are placed on the vertical
line in the plane, or on the ordinate (y axis), as
demonstrated in .
The values are usually arranged so that they increase
from left to right and from bottom to top. The values
may be spaced arbitrarily along each
axis to optimize any observable relationships
between the two variables.
 In pharmacokinetics, time is the independent
variable and is plotted on the abscissa (x axis),
whereas drug concentration is the dependent
variable and is plotted on the ordinate (y axis).
 Two types of graph paper are usually used in
pharmacokinetics. These are Cartesian or
rectangular coordinate graph paper and
semilog graph paper
 Semilog paper is available with one, two, three, or
more cycles per sheet, each cycle representing a
10-fold increase in the numbers, or a single log10
unit. This paper allows placement of the data at
logarithmic intervals so that the numbers need not
be converted to their corresponding log values
prior to plotting on the graph.
 Graphical representation of drug plasma time data
is required for the assessment of compartment and
pharmacokinetic data.
 It is usual to plot the concentration data on the
logarithmic scale or converting each value to into
log natural and then plotting it on ordinary scale.
 The semilogarithmic paper enables plotting of the
concentration data directly without log natural
conversion.
Practice problem
Table: Plasma level time data
Concentration (ug/mL)
Time (h)
Drug A Drug B
1 16.81 7.38
2 15.68 6.91
3 14.52 6.44
4 13.39 6.02
5 12.3 5.41
6 11.21 4.92

1.Graph drug A and drug B data on Semilog paper (two

cycles) and rectangular graph paper
2.Calculate %decline of drug A and drug B from 1h to 6
h using formula
%decline = 100 x (Con. at 1 h – Con. at 6 h)/Con. at 1 h
3. Calculate slope of drug A and drug B on rectangular
graph paper
Slope = Rate of decline = Y2 – Y1/X2-X1
4. Calculate slope of drug A and drug B on semilog graph
paper
Slope = Rate of decline = LnY2 – LnY1/X2-X1
5. Compare rate of decline drug A and drug B using
above data
Determination of the Slope
1.Slope of a Straight Line on a Rectangular
Coordinate Graph
The value of the slope may be determined from any
two points on the curve. The slope of the curve is
equal to y/x, as shown in the following equation:

The slope of the line plotted in is

2. Slope of a Straight Line on a Semilog Graph
When using semilog paper, the y values are plotted
on a logarithmic scale without performing actual
logarithmic conversions, whereas the corresponding
x values are plotted on a linear scale. Therefore, to
determine the slope of a straight line on semilog
paper graph, the y values must be converted to
logarithms, as shown in the following equation:

The slope value is often used to calculate k, a

constant that determines the rate of drug decline:
Rates and Orders of Reactions
Rate
The rate of a chemical reaction of process is the
velocity with which the reaction occurs. Consider the
following chemical reaction:

If the amount of drug A is decreasing with respect to

time (that is, the reaction is going in a forward
direction), then the rate of this reaction can be
expressed as
 Since the amount of drug B is increasing with
respect to time, the rate of the reaction can also be
expressed as

Rate Constant
The order of a reaction refers to the way in which the
concentration of drug or reactants influences the
rate of a chemical reaction or process.
Zero-Order Reactions (Derivation of Equation)
If the amount of drug A is decreasing at a constant
rate, then the rate of disappearance of drug A is
expressed as
-dA/dt ∝ [A]0
-dA/dt = K0
-dA = K0.dt
dA = -K0.dt
Taking integration on both sides
∫dA = -K0 ∫dt
[A] = [Ao] – K0t
A=A –Kt
where A0 is the amount of drug at t = 0. Based on
this expression, a graph of A versus t yields a straight
line. The y intercept is equal to A0, and the slope of
the line is equal to k0.
Equation may be expressed in terms of drug
concentration, which can be measured directly.

C0 is the drug concentration at time 0, C is the drug

concentration at time t, and k0 is the zero-order
decomposition constant.
Example
A pharmacist weighs exactly 10 g of a drug and
dissolves it in 100 mL of water. The solution is kept
at room temperature, and samples are removed
periodically and assayed for the drug. The pharmacist
obtains the following data:
From these data, a graph constructed by plotting the
concentration of drug versus time will yield a straight
line. Therefore, the rate of decline in drug
concentration is of zero order.
The zero-order rate constant k0 may be as given
below
If

And

then
And

Careful examination of the data will also show that

the concentration of drug declines 5 mg/mL for each
2-hour interval. Therefore, the zero-order rate
constant may be obtained by dividing 5 mg/mL by 2
hours:
 In Zero-Order Kinetics, the rate of elimination is
independent of plasma concentration (or amount in
the body) and constant amount of drug is
eliminated per unit time. For example, if 80 mg is
administered IV and 10 mg is eliminated every 1
h, the time course of drug elimination is
 Drugs with zero-order elimination have no
constant half- life.
 Drugs with zero-order elimination include ethanol
(except low blood levels), phenytoin (high
therapeutic doses), and salicylates (toxic doses).
 Special care is needed while increasing the dose of
drugs which follow zero order kinetics to avoid
adverse drug reactions.
Example
A patient was administered with 10 g of drug (IV
bolus). After administration; the blood samples are
removed periodically and assayed for drug. The
following data was obtained

Time (Hrs) 0 2 4 6 8 10 12 14 16
Plasma con. of drug 100 90 80 70 60 50 40 30 20
(mg/mL)
Log of Plasma con. of 2 1.95 1.9 1.84 1.77 1.7 1.6 1.47 1.3
drug (mg/mL)

Draw the above data on semilog and rectangular graph paper

First-Order Reactions (Derivation of Equation)
If the amount of drug A decreasing is directly
propotional to drug A is expressed as
-dA/dt ∝ [A]
-dA/A= K.dt
dA /A = -K.dt
Taking integration on both sides
∫dA /A = -K ∫dt
ln [A] = - kt + C
where k is the first-order rate constant and is
expressed in units of time-1 (eg, hr-1).
where k is the first-order rate constant and is
expressed in units of time-1 (eg, hr-1).
Evaluate the value of C (the constant of integration)
by using boundry conditions. Specifically, when t =
0, [A] = [A]o. [A]o is the original starting
concentration of A.
Substituting into the equation, we obtain: ln [A]o = -
k (0) + C.
Therefore, C = ln [A]o
We now can write the integrated form for first-order
kinetics, as follows:
ln [A] = - kt + ln [A]o
 Where InA0 is (Integration constant).

When drug decomposition involves a solution,

starting with initial concentration C0, it is often
convenient to express the rate of change in drug
decomposition, dC/dt, in terms of drug concentration,
C, rather than amount because drug concentration is
assayed. Hence,
Above Equation may be expressed as

Because ln = 2.3 log, Equation so

A graph of log A versus t will yield a straight line,
the y intercept will be log A0, and the slope of the
line will be –k/2.3. Similarly, a graph of log C versus
t will yield a straight line.
The y intercept will be log C 0, and the slope of the
line will be –k/2.3. For convenience, C versus t may
be plotted on semilog paper without the need to
convert C to log C. An example is shown in
.

According to above
Equation , a graph of log A
versus t will yield a straight
line, the y intercept will be
log A 0, and the slope of the
line will be –k/2.3.
In First Order Kinetics, the rate of elimination is
dependent on plasma concentration (amount in the
body) and constant % age of drug is eliminated per
unit time. For example, if 80 mg is administered IV
and 10 mg is eliminated every 1 h, the time course of
drug elimination is
 Drugs with First-order kinetics have constant half-
life. Most of the drugs are removed from the body
by first order kinetics. The half life of a drug is
given by
 Where Ke is elimination rate constant.
0.693
t½ = --------------
Ke
 After a single dose, nearly complete ((97 %)
clearance is expected by the end of 5 t1/2 interval.
 A graph of log A versus t will yield a straight line,
the y intercept will be log A 0, and the slope of the
line will be –k/2.3.
Problem
A patient was administered with 10 g of drug (IV
bolus). After administration; the blood samples are
removed periodically and assayed for drug. The
following data was obtained

Time (Hrs) 0 4 8 12 16 20 24
Plasma con. of drug (mg/mL) 100 50 25 12.5 6.25 3.13 1.56
Log of Plasma con. of drug 2 1.7 1.4 1.1 0.8 0.5 0.2
(mg/mL)

Draw the above data on semi-log and rectangular graph paper

Half-Life
Half-life (t 1/2) expresses the period of time required
for the amount or concentration of a drug to decrease
by one-half.
To determine the various parameters of First
order clearance and Zero order clearance
(plasma half-life, slope, rate, intercept, rate
constant)
Theory:
1. Elimination half-life or plasma half-life:
Time required for the concentration of drug to be
decreased half of its initial value is called the
elimination half-life (t1/2). For example, if 80 mg of
a drug is administered and its time course of its
elimination is
Elimination half-life = 1 h
Plasma half-life is constant for First order kinetics
and is variable for zero order kinetics. The plasma
concentration is assumed to zero after five half-lives.
Importance:
1. Plasma half-life shows how quickly a drug is
removed from plasma by biotransformation or
excretion.
2. It indicates the duration of action of drugs
3. It also helps us to adjust time interval b/w two
doses.
A. Calculation of Plasma half-life for first order
kinetics:
We know that
So
LogA-LogA0= -Kt/2.3
LogA0 - LogA = Kt/2.3
LogA0/A = Kt/2.3
2.3 LogA0/A = Kt
t =2.3/K LogA0/A
At t1/2, A= Ao/2
So
t1/2= 2.3/K LogA0/Ao/2
 t1/2= 2.3/K Log2
 t1/2= 0.693/K
Where K is elimination rate constant for first order
kinetics
 It is clear from the above equation that plasma
half-life for first order kinetics is constant and is
independent concentration of drug present in the
body
Example
A pharmacist dissolves exactly 10 g of a drug into
100 mL of water. The solution is kept at room
temperature, and samples are removed periodically
and assayed for the drug. The pharmacist obtains the
following data:
With these data, a graph constructed by plotting the
logarithm of the drug concentrations versus time will
yield a straight line on rectangular coordinates. More
conveniently, the drug concentration values can be
plotted directly at a logarithmic axis on semilog
paper against time, and a straight line will be
obtained (). The relationship of time versus drug
concentration in indicates a first-order reaction.
The t1/2 for a first-order process is constant and may
be obtained from any two points on the graph that
show a 50% decline in drug concentration. In this
example, the t 1/2 is 4 hours. The first-order rate
constant may be found by (1) obtaining the product
of 2.3 times the slope or (2) by dividing 0.693 by the
t 1/2, as follows:
B. Calculation of Plasma half-life for zero order
kinetics
We know that

So
Ao – A = Kot
Ao – A/ko = t
We know that at t1/2, A= Ao/2
Ao – Ao/2/ko = t1/2
t1/2= 1/2A0/Ko
t1/2= 0.5A0/Ko
Where K0 is elimination rate constant for zero order kinetics
It is clear from the above equation that plasma half-
life for zero order kinetics is directly proportional to
concentration of drug present in the body. Because
the t 1/2 changes as drug concentrations decline, the
zero-order t 1/2 has little practical value.
2. Rate constant:
It determines the rate of drug decline
A. Rate constant for First order Kinetics:
It can be calculated by two methods

B
B. Rate constant for Zero order Kinetics
If the amount of drug A is decreasing at a constant
time interval t, then the rate of disappearance of drug
A is expressed as

The term k 0 is the zero-order rate constant and is

expressed in units of mass/time (e.g, mg/min).
Integration of Equation 2.19 yields the following
expression:

where A 0 is the amount of drug at t = 0 (Integration

constant) and A is the drug concentration at time t.
3. Slope
It simply whether the concentration of drug is
increasing (+) or decreasing (-) with respect to time.
The slope value is often used to calculate k, a
constant that determines the rate of drug decline
Determination of the Slope
:
A. Slope of a straight line on a rectangular
coordinate graph
The value of the slope may be determined from any
two points on the curve. The slope of the curve is
equal to ∆y/∆x, as shown in the following equation:
B. Slope of a straight line on a semi-log graph
When using semi-log paper, the y values are plotted
on a logarithmic scale without performing actual
logarithmic conversions, whereas the corresponding
x values are plotted on a linear scale. Therefore, to
determine the slope of a straight line on semi-log
paper graph, the y values must be converted to
logarithms, as shown in the following equation
4. Intercept:
It is the concentration of drug in body at time zero.
Determination of intercept:
It can be determined through extrapolation of the
graph to Y-axis at time zero.
Problems
1. A patient was administered with 10 g of drug (IV
bolus). After administration; the blood samples are
removed periodically and assayed for drug. The
following data was obtained
Time (Hrs) 0 2 4 6 8 10 12 14 16
Plasma con. of drug 100 90 80 70 60 50 40 30 20
(mg/mL)
Log of Plasma con. of 2 1.95 1.9 1.84 1.77 1.7 1.6 1.47 1.3
drug (mg/mL)

A. Draw the above data on semi-log and rectangular graph paper

B. Determine the slope of the curve
C. Determine the Intercept of the curve from semilog and rectangular
graph
D. Calculate the Rate constant and Plasma half-life of drug
2. A patient was administered with 10 g of drug (IV
bolus). After administration; the blood samples
are removed periodically and assayed for drug.
The following data was obtained

Time (Hrs) 0 4 8 12 16 20 24
Plasma con. of drug (mg/mL) 100 50 25 12.5 6.25 3.13 1.56
Log of Plasma con. of drug 2 1.7 1.4 1.1 0.8 0.5 0.2
(mg/mL)

A. Draw the above data on semilog and rectangular graph paper

B. Determine the slope of the curve
C. Determine the Intercept of the curve from semilog and
rectangular graph
D. Calculate the Rate constant and Plasma half-life of drug
3. Plot the following data on both semilog graph
paper and standard rectangular coordinates and
determine whether the decrease in the amount of drug
a appear to be a zero-order or a first-order process?
Also determine the slope of the curve, intercept, rate
constant and plasma half-life of the drug
Time Drug A (mg/L)
(min)
10 96
20 89
40 73
60 57
90 34
120 10
130 2.5
Time Drug A (mg/L)
(min)

0.5 84.5
1 81.2
2 74.5
4 61
6 48
8 35
12 8.7