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Pharmacokinetics Lab I

Background

What is Pharmacokinetics?
The fate of a drug over time through the body (what the body does to the drug).
4 main processes: ADME
Absorption: how it gets in to the bloodstream
Distribution: how it gets around the body
Metabolism: changed by body to help
Elimination / Excretion: how it gets out

Learning outcomes:
1. The purpose of these labs is to develop knowledge and understanding of
pharmacokinetics, and the effect that route of administration has on drug
availability.
2. After you have completed this section you should be able to:
a. Represent graphically plasma drug concentration versus time curve
after intravenous
b. Understand and calculate pharmacokinetic parameters such as half
life, area under the curve, clearance and volume of distribution

1 . Intravenous Bolus
Example:
The following table presents data obtained after an intravenous bolus dose of 250
mg ceftriaxone (an antibiotic) in an adult male.

Time
(h)
0.25 0.50 0.75 1.00 1.50 2.00 3.00 4.00 6.00 8.00
Conc.
(mg/L)
10.2 8.8 7.8 6.6 4.9 3.6 2.0 1.15 0.34 0.105

(a) Prepare a semilogarithmic plot of the plasma concentration of ceftriaxone versus time.
(b) Estimate the elimination half-life (t ) of the drug.
(c) Estimate the elimination rate constant (Kel)
(d) Estimate the total AUC of ceftriaxone using both the equation
(e) and trapezoidal rule.
(f) Calculate the total clearance.
(g) Calculate the volume of distribution.

Useful equations:

T
1/2
=0.693/kel
T
1/2
=(0.693 x Vd)/Cl
Dose =Cl x AUC
Vd =Cl/Kel
AUC =C
0
/Kel
Kel =0.693/t
1/2
Dose =Vd x Cp(0)
Note: Some of these equations apply to an intravenous bolus dose only.
Solution:
(a) Semilog plot: See graph
Example 1
0 2 4 6 8 10
0.01
0.1
1
10
100
1.2 h
Time (h)
C
p

(

g
/
m
l
)

(b) Half-life =the length of time it takes for the plasma concentration (Cp) to fall by half.

the time it takes for Cp to fall from 2 g/mL to 1 g/mL.
=4.2 h - 3 h (see graph)
=1.2 h

(c) Kel =0.693/t
1/2

Kel =0.693/1.2 h =0.5775 h
-1

(d) There are two ways the AUC can be calculated:
Use the equation AUC =C
0
/kel (for an i.v. dose)
Use the trapezoidal rule (see below)

Using AUC =C
0
/kel,
Extrapolate to the Y axis; Cp at time 0 =12 g/mL; =12 mg.L
-1

AUC =12 mg.L
-1
/kel

AUC =12 mg.L
-1
/0.5775 h
-1
AUC =20.779 mg.h.L
-1

(e) A similar value should be obtained using the trapezoidal rule. Usually however, the
trapezoidal rule yields a slightly higher value. This is because, at any time, the concentration
along the straight line connecting two data points is always greater than the corresponding
concentration on the declining exponential curve.
(
m
g
/
L
)

Trapezoidal Rule
Get the area for each segment on the graph; (see below for how to)
Add up the areas
This gives you the area under the curve from time 0 to time t (8 h in this case)
Calculate the area from the last time to infinity using the equation.
Li near graph paper Trapezoi dal Rul e
0 1 2 3 4 5 6 7 8
0
5
10
15
Ti me (h)
C
o
n
c
e
n
t
r
a
t
i
o
n

(
m
g
/
L
)

AUC iv bolus
Time (h) Cp (mg/L) time int avg conc AUC
0 12 0.25 11.1 2.775
0.25 10.2 0.25 9.5 2.375
0.50 8.8 0.25 8.3 2.075
0.75 7.8 0.25 7.2 1.8
1.00 6.6 0.5 5.75 2.875
1.50 4.9 0.5 4.25 2.125
2.00 3.6 1 2.8 2.8
3.00 2 1 1.575 1.575
4.00 1.15 2 0.745 1.49
6.00 0.34 2 0.2225 0.445
8.00 0.105

AUC 0-8h 20.335

= () = () +
()1
2
(1 0)
1
0

Calculate the time interval between successive Cp values
Get the average concentration between successive times (t1-to; t2-t1; etc.
To get the AUC multiply the avg conc by the time interval
Calculate the residual AUC from time t to infinity:
=
()

=0.105/0.5775
=0.1818
Total AUC =AUC 1-8 +AUC residual
=20.335 +0.182
=20.517 mg L
-1
h
NB Do not round until the end or you will get rounding errors.

(f) Dose =Clearance (Cl) x AUC
Cl =Dose/AUC
=250 mg/20.517 mg.L
-1
h

Clearance =12.185L.h
-1

Remember: Always check your units. If the dose is given in mg but the AUC is given in g.h.L
-
1
, you will need to multiply the dose x 1000 to give you g. [i.e. 1 mg =1000 g or 1 x 10
3
g.]

(g) Volume of distribution (Vd) =Cl/kel
=12.185L.h
-1
/ 0.5775 h
-1

=21.0996 L

=21.1L

Exercise 1. For you to practise.

The table below gives plasma drug concentrations (Cp) following an iv bolus administration of a
250 mg dose of a drug. Prepare a semilog plot of plasma concentration (Cp) versus time:

a. Comment on the purpose of using semilog graph paper.

Determine the following.

b. The elimination half-life (t)

Ans: ~1.3 h
c. The elimination rate constant (Kel)

(0.5331 h
-1
)
d. The initial plasma concentration (Co)

(Co =90ug/mL)
e. The apparent volume of distribution (Vd)

(Vd =Dose /Co =2.77 L

Time (h) 0.5 1.0 2.0 3.0 5.0 7.0
Cp (g/mL) 68.0 54.0 30.0 18.5 6.0 1.8