GENERAL PHARMACOLOGY

Pharmacokinetics
PHARMACOKINETICS
investigate the relationship between the time
course of drug concentrations attained in different
regions of the body during and after dosing

it deals with the actions of the body on the drug
including:
absorption from the site of administration
distribution within the body
metabolism
excretion
2
0
1
2
-
1
1
-
0
4

2
PHARMACOKINETICS
are used during drug development to determine the
optimal formulation of drug, dose and dosing
frequency

especially important for drugs with narrow
therapeutic index

1
1
/
4
/
2
0
1
2

3
2
0
1
2
-
1
1
-
0
4

4
INTRAVENOUS DOSING single-compartment model
100
0
Plasma
concentration
(mol/l)
Hours (h)
10
0
8 16 24
Y-axis is logarithmic scale
1
1
/
4
/
2
0
1
2

5
100
0
Plasma
concentration
(mol/l)
Hours (h)
10
0
8 16 24
AUC
C
max
T
max
C
max
maximum concentration achieved
T
max
time required to achieve maximum concentration
AUC area under curve
EXTRAVASCULAR DOSING single-compartment model
Y-axis is logarithmic scale
AREA UNDER THE CURVE (AUC)
indicator of overall exposure of a person to a drug
mathematically integrated area under the
concentration-time curve and calculated using
trapezoidal rule of mathematics
two drugs with entirely different shape of the curve
may have the same AUC value
the same drug in different formulations may have
different AUC
AUC is useful also for calculating clearance
1
1
/
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/
2
0
1
2

6
SINGLE COMPARTMENT MODEL
Volume of distribution
Vd
Dose oral (Q)
Dose intravenous (Q)
Absorption k
abs
Excretion Metabolism
k
exc
k
met
2
0
1
2
-
1
1
-
0
4

7
SINGLE COMPARTMENT MODEL
drug concentration after time (t) is calculated
according to formula:


C
(t)
concentration after time (t)
C
(0)
initial concentration
K
e
elimination constant (excretion and metabolism)

taking logarithms:

C
(t)
= C
(0)
e
-K
e
t
lnC
(t)
= lnC
(0)
K
e
t
1
1
/
4
/
2
0
1
2

8
SINGLE COMPARTMENT MODEL
(K = 0,2 h
-1
)
(K = 0,05 h
-1
)
(K = 0,05 h
-1
)
t
0,5
value
for a
t
0,5
value
for b & b
0
2
4
6
8
10
3,5 13,9 50 25
Hours (h)
a
b
b
Plasma
concentration
(mol/l)
2
0
1
2
-
1
1
-
0
4

9
SINGLE COMPARTMENT MODEL
0
10
50
25
0,2
0,5
1
2
5
b
b
a
Plasma
concentration
(mol/l) (log
scale)
Hours (h)
2
0
1
2
-
1
1
-
0
4

10
HALF-LIFE TIME OF A DRUG
half-life time of a drug (t
0,5
) means time needed
to eliminate half (50%) of given drug dose
it does not mean that tha same amount of drug is eliminated
each half-life
it takes about 5 half-lives to eliminate 97% of drug
1
1
/
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/
2
0
1
2

11
100
0
Plasma
concentration
(mol/l)
Hours (h)
10
0
8 16 24
50%
8 hours
t
0,5
= 8 hours
HALF-LIFE TIME OF A DRUG
taking the formula:


which means:
1
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/
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/
2
0
1
2

12
K
e
x t = lnC
(0)
lnC
(t)

K
e
C
(0)
ln
C
(t)
t =
HALF-LIFE TIME OF A DRUG
to get t
0,5
we have to put as C
(t)
C
(0)
/2
(half of initial dose)






ln2 = 0,693 so:
1
1
/
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/
2
0
1
2

13
K
e
2C
(0)
ln
C
(0)
K
e
ln2
t
0,5
= =
K
e
0,693
t
0,5
=
ELIMINATION CONSTANT K
E
elimination constant K is calculated from formula:





CL clearance of a drug
V
d
volume of distribution
1
1
/
4
/
2
0
1
2

14
V
d
CL
K
e
=
HALF-LIFE TIME OF A DRUG
can calculate half-life time of a drug knowing its
clearance and volume of distribution:



in first-order kinetic half-life time remains constant if
constant are volume of distribution and/or clearance

age, diseases and other factors can change both volume of
distribution and clearance of a drug and in this way
shorten or lengthen the half-life time in various patients
1
1
/
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/
2
0
1
2

15
CL
0,693 x V
d
t
0,5
=
STEADY STATE
half-life is necessary to estimate/predict:
how long a drug is expected to remain in the organism
after termination of dosing
time required to reach steady state
the rate of drug entering to the body is equal to the rate of
drug leaving the body
often after about 5 half-lives
the frequency of dosing
1
1
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/
2
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1
2

16
EFFECT OF REPEATED DOSAGE
1
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1
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next dose of drug is administered before the drug is essentially
(97%) eliminated
in steady-state maximun and minimum concentrations become
consistent
to achieve steady-state earlier a bolus with initial dose is
necessary
Days
5
10
0
infusion
at 200 mol/24 h
injection 100 mol
twice daily
injection 200 mol
once daily
Plasma
concentration
(mol/ml)
injection of loading dose
followed by infusion
EFFECT OF VARIATION IN RATE OF ABSORPTION
10
0
Plasma
concentration
(mol/l)
Hours (h)
5
0
8 16 24
to
0,5
absorption
0 h
1 h
3 h
6 h
effective conc.
2
0
1
2
-
1
1
-
0
4

18
BIOAVAILABILITY - F
bioavailability is the fraction of administered dose
that reaches the systemic circulation intact, taking
into account both absorption and local metabolic
degradation
depends on route of administration and the
formulation
F is measured by determining the plasma drug
concentration versus time curves in a group
of subjects following oral and intravenous
administration
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BIOAVAILABILITY - F
only for intravenous route bioavailability is
considered as 1 (100%)

e.g. propranolol (first-pass metabolism)
I.V. administration F = 1
oral administration F = 0.2
e.g. digoxin
oral administration as solution F = 1
oral administration as tablets F = 0.7
1
1
/
4
/
2
0
1
2

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BIOAVAILABILITY
10
0
Plasma
concentration
(mol/l)
Hours (h)
5
0
8 16 24
AUC i.v.
AUC p.o.
2
0
1
2
-
1
1
-
0
4

21
ABSOLUTE VS. RELATIVE BIOAVALIABILITY
two products are compared to each other not to IV
route
used to compare e.g. if generic formulation is
bioequivalent to the original formulation
1
1
/
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/
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22
AUC
iv
AUC
other
F =
dose
other
x AUC
iv
dose
iv
x AUC
other
F =
ABSOLUTE
RELATIVE
CLEARANCE = ELIMINATION
the volume of blood from which drug is completely
removed per unit of time (e.g. mL/minute)
describes the efficiency of irreversible elimination
of drug
may involve metabolism and excretion
uptake a drug into tissues does not constitute
clearance
total (systemic) clearance = clearance of drug
by all routes
1
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/
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1
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CLEARANCE = ELIMINATION
1
1
/
4
/
2
0
1
2

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CL = K
e
x V
d
or
for other administration the apparent clearance is:
for intravenous administration clearance is:
apparent because the bioavailability is not known
for renal excretion clearance is:
AUC

dose
CL

=
AUC

dose x F
CL
app
=
AUC

dose
CL
app

=
F
AUC

A
e
CL
r
=
A
e
total amount of drug excreted unchanged renally
VOLUME OF DISTRIBUTION (V
D
)
relates a concentration of drug measured in blood
to the total amount of drug in the body

the greater Vd the greater the diffusibility of the
drug

its not an actual volume
its estimation may be greater than the volume
available in the body
1
1
/
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/
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0
1
2

25
VOLUME OF DISTRIBUTION (V
D
)
real volume of distribution the volume of the
body which the drug reaches

apparent volume of distribution (V
d
) mathematical
value; relation between the administered dose and
measured concentration in blood (V
d
= D/C
i
)

relative volume of distribution (V
d
/kg)



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PROTEIN BINDING
1
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dose of drug A 1000 mg
drug A binds with the
proteins with 95%
free fraction 50 mg
0.01mg/mL (if blood is 5L)
drug B displace drug A
protein binding is 90%
free fraction 100 mg
0.02 mg/mL - doubled
dose of drug A 1000 mg
drug A binds with the
proteins with 30%
free fraction 700 mg
0.14mg/mL if blood is 5L
drug B displace drug A
protein binding is 25%
free fraction 750 mg
0.15 mg/mL difference
about 7%

HIGH PROTEIN BINDING LOW PROTEIN BINDING
THE TWO-COMPARTMENT MODEL
Excretion Metabolism
Central
compartment (1)
Oral dose
Intravenous dose
Absorption k
abs
k
exc
k
met
Peripheral
compartment (2)
k
21
k
12
2
0
1
2
-
1
1
-
0
4

28
TWO-COMPARTMENT MODEL KINETICS
0
5
24
Plasma diazepam
concentration (mol/l)
Time (h)
2
1,0
0,5
0,2
12
Experimental data
Slow phase
t
0,5
= 30 h
Fast phase
t
0,5
= 1,2 h
1
1
/
4
/
2
0
1
2

29
ZERO AND FIRST ORDER KINETICS
first-order kinetics (the rate of drug elimination
is proportionate to the drug concentration)
most drugs (within therapeutic range)
elimination of the same percentage of dose

zero-order kinetics (the rate of drugs elimination
is constant regardless of concentration)
e.g. ethanol, phenytoin and salicylate
elimination of the same amount of drug
duration of action strongly dependents on dose
the relationship between dose and steady-state
plasma concentration is steep and unpredictable
1
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30
ZERO-ORDER KINETICS
Plasma ethanol
concentration
(mol/l)
20
0
Time after ingestion (min.)
10
0
60 90 120
administered
dose
Absorption
Dose (mmol/kg)
14,1
10,9
7,6
4,3
1
1
/
4
/
2
0
1
2

31
constant amount of drug is eliminated per unit of time
(T
0,5
of drug is unstable = couldnt be assesed)
first-order elimination following single IV bolus dose
FIRST-ORDER KINETICS
2
0
1
2
-
1
1
-
0
4

32
constant fraction or percent of drug is eliminated per unit of time
(T
0,5
of drug is stable)
20
0
10
60 90 120
Time
Plasma drug
concentration
(mol/l)
0
0
1
60 90 120
Time
Log of plasma drug
concentration
0
1
1
/
4
/
2
0
1
2

33
given dose 1000 mg
every hour is eliminated
100 mg of given dose
amount of drug remaining
in the body after:
1 hour 900 mg
2 hours 800 mg
3 hours 700 mg
4 hours 600 mg
5 hours 500 mg
etc.
eliminated: 100 mg, 200mg,
300 mg, 400 mg, 500 mg,
respectively
given dose 1000 mg
half-life 1 hour
every hour is eliminated 50%
of the current dose
amount of drug remaining in the
body after:
1 hour (1 T
0,5
) 500 mg
2 hours (2 T
0,5
) 250 mg
3 hours (3 T
0,5
) 125 mg
4 hours (4 T
0,5
) 62.5 mg
5 hours (5 T
0,5
) 31.25 mg
etc.
eliminated: 50%, 75%, 87.5%,
93.75%, 96.875%, respectively


ZERO-ORDER KINETICS FIRST-ORDER KINETICS
THERAPEUTIC WINDOW
20
0
Plasma
concentration (mg/l)
Time (h)
10
0
5 10 15
Minimum effective
concentration
Minimum toxic
concentration
Therapeutic
window
2
0
1
2
-
1
1
-
0
4

34
therapeutic window is the safe space between:
the minimum therapeutic concentration and
the minimum toxic concentration of a drug
NONLINEAR PHARMACOKINETICS
for some drugs in the range of therapeutic dose
a small increase in a dose causes greater than
expected increase in blood concentration

it suggests nonlinear pharmacokinetics
e.g. increase phenytoin dose from 300 mg to 400 mg
(33%) causes 300% increase in blood concentration
may be because the drug metabolizing enzymes
become saturated
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Rang & Dales Pharmacology, Churchill Livingstone, Elsevier,
6th Ed, 2007
Katzung & Trevors Pharmacology, Examination and Board
Review, McGraw Hill, Lange, 9th Ed, 2010
Modern Pharmacology with Clinical Applications, LWW,
6th Ed, 2004
Podstawy farmakologii dla lekarzy, farmaceutw i studentw
medycyny, Volumed, 1996
Basic and Clinical Pharmacology, McGraw Hill, Lange,
11th Ed, 2009
Stedmans Medical Dictionary, LWW, 28th Ed, 2006
Lippincotts Illustrated Reviews: Pharmacology, LWW,
3rd Ed, 2000
Goodman & Gilmans The Pharmacological Basis
of Therapeutics, McGraw Hill, 11th Ed, 2006
4

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b
e
r

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REFERENCES