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OVERVIEW
Basic considerations in pharmacokinetics
Compartment models
One compartment model
Assumptions
Intravenous bolus administration
Intravenous infusion
Extravascular administration (zero order and
first order absorption model)
References
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BASIC CONSIDERATIONS IN
PHARMACOKINETICS
Pharmacokinetic parameters
Pharmacodynamic parameters
Zero order kinetic
First order kinetic
Mixed order kinetic
Compartment model
Non compartment model
Physiologic model
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Pharmacokinetic models
Means of expressing mathematically or quantitatively,
time course of drug through out the body and compute
meaningful pharmacokinetic parameters.
Useful in :
Characterize the behavior of drug in patient.
Predicting conc. of drug in various body fluids with
dosage regimen.
Calculating optimum dosage regimen for individual
patient.
Evaluating bioequivalence between different formulation.
Explaining drug interaction.
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Compartment models
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OBJECTIVE
To understand the assumptions associated with the one
compartment model
To understand the properties of first order kinetics and linear
models
To write the differential equations for a simple pharmacokinetic
model
To derive and use the integrated equations for a one
compartment linear model
To define, use, and calculate the parameters, Kel (elimination
rate constant), t1/2 (half-life), Cl (clearance), V (apparent volume
of distribution), and AUC (area under the concentration versus
time curve) as they apply to a one compartment linear model
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One Compartment
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PHARMACOKINETICS
Pharmacokinetics is the study of drug
and/or metabolite kinetics in the body.
The body is a very complex system and a
drug undergoes many steps as it is being
absorbed, distributed through the body,
metabolized or excreted (ADME).
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Assumptions
1. One compartment
The
This
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2. Rapid Mixing
We
3. Linear Model
We
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First-order kinetics
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(eq.1)
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Elimination phase:
Elimination phase has three parameters:
Elimination rate constant
Elimination half life
Clearance
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(eq.2)
log X= log Xo KE t
2.303
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(eq.4)
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(eq. 5)
So equation-8 becomes
log C = log Co KE t
2.303
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(eq.6)
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(eq.9)
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Apparent volume of
distribution
Defined as volume of fluid in which drug appears to
be distributed.
Vd = amount of drug in the body = X
plasma drug concentration
C
(eq.10)
Vd = Xo/Co
=i.v.bolus dose/Co
(eq.11)
23
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Clearance
Clearance = rate of elimination
plasma drug conc..
Or Cl= dx /dt
C
(eq.13)
Thus
Renal clearance
= rate of elimination by kidney
C
Hepatic clearance = rate of elimination by liver
C
Other organ clearance = rate of elimination by organ
C
Total body clearance:
ClT = ClR + ClH + Clother
(eq.14)
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ClR =Ke Vd
but KE= 0.693/t1/2
so,
ClT= 0.693 Vd
(eq.18)
(eq.19)
t1/2
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(eq. 21)
AUC
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Organ clearance
Rate of elimination by organ= rate of presentation to the
organ rate of exit from
the organ.
Rate of elimination =Q. Cin- Q.Cout
(rate of extraction) =Q (Cin- Cout)
Clorgan=rate of extraction/Cin
=Q(Cin-Cout)/Cin
=Q.ER
.(eq 22)
Extraction ratio:
ER= (Cin- Cout)/ Cin
ER is an index of how efficiently the eliminating organ
clear the blood flowing through it of drug.
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According to ER, drugs can be classified as Drugs with high ER (above 0.7)
Drugs with intermediate ER (between 0.70.3)
Drugs with low ER (below 0.3)
The fraction of drug that escapes removal by
organ is expressed as
F= 1- ER
where F= systemic availability when the
eliminating organ is liver.
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Hepatic clearance
ClH = ClT ClR
o
o
o
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R0
Drug
Zero order
KE
Infusion
rate
dX/dt=Ro-KEX
X=Ro/KE(1-e-KEt)
eq 23
eq 24
Since X=VdC
C=Ro/KEVd(1-e-KEt) eq 25
=Ro/ClT(1-e-KEt)
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eq 26
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[CSS-C]=e-KEt .
...32
CSS
log CSS-C =
-KEt 33
CSS
2.303
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Xo,L=CSSVd
Substitution of CSS=Ro/KEVd
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Xo,L=Ro/KE
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C=Xo,L/Vd e-KEt+ Ro/KEVd(1-e-KEt) 37
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Assessment of pharmacokinetic
parameter
AUC=Ro T/KE Vd
=Ro T/ClT
=CSS T
Where T=infusion time
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dXev/dt >dXE/dt
dXev/dt=dXE/dt
dXev/dt<dXE/dt
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R0
Elimination
zero order
absorption
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First order
KE
elimination
absorption
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40
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Contents
Introduction
Multi- Compartment models
Two-Compartment Open model
Intravenous bolus administration
Extravascular administration
References
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Central
peripheral
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Vp
Vc
Vc
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ba
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a-b
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[(
Cp = X o
K21 a)e-at + (K12 b)e-bt]
Vc
ba
ab
Xo = iv bolus dose
a and b = hybrid first order constants for
rapid dissolution phase and slow
elimination phase, which depend entirely
on 1st order constants K12, K21, KE
The constants K12, and K21 that depict the
reversible transfer of drug between the
compartments are called micro or transfer
constants.
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A = X0 K21 - a
Vc
= Co K21 a
ba
B = X0 K21 - b
ba
= Co K21 b
Vc a b
ab
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C0 = A + B
KE =
abc
Ab+Ba
K12 = A B (b - a)2
C0 (A b + B a)
K21 = A b + B a
C0
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App. volume of
= VP = VC K12
Peripheral compartment
K21
Apparent volume of distribution at steady
state or equilibrium
Vd,ss = VC +VP
Vd,area = X0
b AUC
Total systemic Clearence= ClT = b Vd
Renal Clearence= ClR =dXU = KE VC
dt
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Central
Peripheral
ba
a-b
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1
Central
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DRUG INPUT
CENTRAL
COMPARTMENT
DEEP
TISSUE
COMPARTMENT
TISSUE
COMPARTMENT
K10
THREE COMPARTMENT CATENARY MODEL
RAPID IV
DRUG INPUT
K21
TISSUE
COMPARTMENT
K13
CENTRAL
COMPARTMENT
K12
DRUG OUTPUT
K31
DEEP
TISSUE
COMPARTMENT
K10
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PHARMACOKINETIC PARAMETERS
BIOLOIGICAL HALF-LIFE
It is defined as the time taken for the amount of drug
in the body as well as plasma to decline by one half
or 50% its initial value.
Concentration of drug in plasma as a function of
time is
C=A e - t+ B e - t+ C e - t
In this equation >> some time after the
distributive phase (i.e. when time become large) the
two right hand side terms values are equal to zero.
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VC = D/CO
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Applications of pharmacokinetics
To understand process of absorption,
distribution and elimination after administration of
drug , Which affects onset and intensity of biological
response.
To access drug moiety in terms of plasma drug conc
response which is now considered as more appropriate
parameter then intrinsic pharmacological activity .
In design and utilization of invitro model system that
can evaluate dissolution characteristics of new
compound formulated as new drug formulations and
establish meaningful in vivo-in vitro correlationship.
In design and development of new drug and their
appropriate dosage regimen .
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ABSORPTION
Two physicochemical factors that effect the both extent
and rate of absorption are lipophilicity and solubility .
Increase in the lipophilicity nature of drug results
increase in oral absorption .
e.g. Biophosphonates drug with poor lipophilicity will be
poorly absorbed after oral administration .
absorption of the barbiturates compounds increased
with increasing lipophilicity.
1.
2.
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Higher the lipophilicity of a drug the higher its permeability and the greater its
metabolic clearance due to first pass effect .
The effect of the lipophilicity on membrane permeability and first pass metabolism
appear to have opposing effect on the bioavailability.
Solubility is also an important determinant in drug absorption.
Vavcca successfully developed a novel hydroxyethylene dipeptitide isostere &
selective HIV protease inhibitors.
HIV protease inhibitors are basically lipophilic and poorly soluble resulting in poor
bioavailability.
The solubility of the HIV protease inhibitors can increased by incorporating a basic
amine in to the back bone of this series.
Pro drugs are developed to improve oral absorption .
Eg pivampicillin, becampicillin are the pro drugs of ampicillin.
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Distribution
Lipophilicity of the drug affects the distribution the
higher the lipophilicity of a drug the stronger its
binding to protein & the greater its distribution.
e.g. Thiopental & polychlorinated insecticides.
These drugs are highly distributed and accumulate
in adipose tissue .
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Plasma half-life
Administration of a drug with a short half life requires
frequent dosing and often results in a significant in
patient compliance.
Half life determined by distribution & elimination
clearance.
The prolongation of half life can be achieved by
increasing the volume of distribution & decreasing the
clearance, latter appear to be easier to modify the
chemical structure to slow a drug clearance than to
increase its volume of distribution.
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1.
2.
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References :
Biopharmaceutics and pharmacokinetics.
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THANK YOU
Cell No: 0091 9742431000
E-mail: bknanjwade@yahoo.co.in
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