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PHARMACOKINETICS

Dr. Henny Lucida, Apt

Topics

Introduction to pharmacokinetics
Pharmacokinetic models
One-compartment open model
Multicompartmental models
Pharmacokinetic model of oral absorption
Drug Distribution and protein binding
Student presentation & Discussion

Introduction
Various routes of administration
Eye
Nasal
Ear
Oral
Sublingual
Buccal

Intramuscular
Subcutaneous
Intravenous
Intrasynovial
Intracardiac
Intrathecal
Rectal
Vaginal
Urethral
Topical

Dose of drug
administered

Biopharmaceutics

ABSORPTION

Drug conc. in
systemic circulation

DISTRIBUTION

Drug in tissues
Of distribution

Pharmacokinetics

ELIMINATION

Drug conc
at site of action

Drug metabolized
Or excreted

Pharmacologic effect
Pharmacodynamics
Clinical response
Toxicity

Efficacy

Drug conc-response
relationship
MTC

MEC

ADME Processes

Absorption
Distribution
Metabolism
Excretion

Drug Disposition

Pharmacokinetic
model

Compartment models :
Mammillary model
Catenary model
Physiologic model

Mammillary model

One open compartment


model
Assumptions
The drug in the blood is in rapid
equilibrium with drug in the extravascular
tissues
The drug is mixed instantaneously in blood
or plasma
Drug elimination follows first order
kinetics

Multicompartment model
Assumptions
The drug would be transferred to other
compartments (k12, k21, k13, k31)
The transferred lasted when equilibrium is
reached, at this point the change in drug
conc in central comp will be equal to that in
other comps
Equation for Cp vs t curve is a summation
of several equation of first order kinetics

Two compartment open model

Diagram of a two
compartment model

Parameters
One open compartment model
k0 or ka, kel, t1/2, C, X, Vd app
Multi compartment model
k0 or ka, kel, t1/2, C, X, Vd app, and k12,
k21, k13, k31

Equations
The change of the amount of drug in the
body according to 1st order kin:

X X 0e

k el t

k el t
logX logX 0
2.303

Vd app
X = Vd x C
Vd = a proportionality constant that relate
X and C
C

C C0e

k el t

k el .t
logC logC0
2.303

Vd apparent
Has no physiologic meaning
For some drugs, Vd app exceed the
total body water (60 L)

Vd app of some drugs


Drug

V (L/kg)

V (L/70 kg)

Sulfisoxazole

0.16

11.2

Phenytoin

0.63

44.1

Phenobarbital

0.55

38.5

2.4

168

490

Diazepam
Digoxin

Vd app of digoxin is much larger than


body volume
drug must be extensively
distributed into tissue, leaving low
conc in the plasma, thus the body as
a whole appears to have a large
volume, of distribution

Kel and t1/2 el


Kel is calculated from the slope of the first
order plot of Cp vs t
As for first order kinetics:

t1

0.693

k el

Values for kel and t1/2 el of


some drugs
Drug

kel , hr-1

t1/2 el, hr

Acetaminophen
Diazepam
Digoxin
Gentamicin
Lidocaine
Theophylline

0.28
0.021
0.017
0.35
0.43
0.063

2.5
33
40
2.1
1.6
11

One compartment model,


intravenous injection

Plot of Cp vs t for a bolus iv


dose

Plot of ln C vs t

Equation to calculate kel


k el .t
logC logC0
2.303
Since X0 = the amount of drug injected
intravenously
= the intravenous dose
Then, for an iv bolus:

dose
V
C0

Example calculations:
After an iv dose of 500 mg, V=30 L, kel = 0.2/hr. Calculate Cp at
2 & 4 hr.
Using eq.
And
then
dose
dose k el t
C C 0 e k el t
V
Cp
e
C0
V
C0p = 500/30 = 16.7 mg/L
Cp2hr = 11.2 mg/L
Cp4hr = 7.5 mg/L

Calculation of kel using urinary


excretion data
dX u
k el t
log
logk e X 0
dt
2.303
Kel = ke + knr

Clearance

dX u /dt
Cl r
C

Renal Clearance
Systemic Clearance

Cl r k el Vd app

X0
Cls Vk el
AUC

Vd app

Vd app

X0

k el AUC

Vdapp

X0
k el AUC

AUC

Dose
AUC
V k el

AUC calculated by trapezoidal rule


AUC 0 AUC 0t last AUC t last
Cp 0 Cp1
Cp1 Cp 2 2 1
Cp last

t
t t
2
2
k el

Intravenous infusion

Model:

Profile of Cp vs t for slow iv


infusion

A semilog plot of Cp vs t
for iv infusion

Cp vs t profile for fast iv infusion

Cp vs t profile for iv
infusion with a loading dose

Steady state concentration

Plasma drug conc

k0
Vd app k el

1 e
k el t

During continuous constant rate iv infusion, drug conc in plasma


increase according the above eq but eventually approach a
constant value or plateau called infusion equilibrium, which
actually is a steady-state situation

Css

k0
Vd app k el

Correlation of C and Css

C Css 1 e k el t

Css C k el t
log

Css
2.303
A semilog plot of (Css-C)/Css vs time yields a straight line
with a slope of kel/2.303, then kel can be calculated.

Application of equations

For theophylline with a t1/2= 4 hours, the time to reach Css = 16 hr


(94%)
We could calculate how long it might take to reach a therapeutic
conc (10 mg/L).
Since: k0=60mg/hr, kel=0.17/hr, Vd=25L, and

C
10

1 e

k0

k el t

Vd app k el

60
1 e 0.17t
0.17 25

then,
0.708 = 1-e-0.17*t, thus 0.292 = e-0.17*t
therefore -0.17*t = -1.231 or t = 7.24 hr

C at post infusion
Kel can also be calculated from data collecting after stopping
the infusion
k t'
logC logC max el
2,303
or

k0
k el t'
k el T
logC log
1 e

Vd k el
2.303

Cmax = the drug conc in plasma when the infusion was


terminated
t = the time after stopping the infusion
T = the infusion duration time

Calculation of Vd by using
Css and AUC data
k0
Vd
Css k el

k 0T
Vd
k el AUC

Infusion with a loading dose


Drugs with t1/2 >>>> (long half life)
the time to reach steady state will be very
long
it is desirable to administer an iv loading dose
just before starting the infusion. The loading
dose should be large enough to yield the
desired Css immediately. The infusion rate
should be fast enough to maintain this conc

Loading dose
X0 = Css * Vd
The amount of drug in the body after
simultaneous an iv loading dose and
initiation of constant rate iv infusion:

X X 0e

k el t

k0
k el t

1 e
k el

The amount of drug in the body is constant


throughout the time course of drug adm