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Pharmacokinetic Models
Pharmacokinetic Models
Model
Model approach independent
approach
ADVANTAGES
• Gives visual representation of various rate processes involved in drug disposition.
• Possible to derive equations describing drug concentration changes in each
compartment.
• One can estimate the amount of drug in any compartment of the system after
drug is introduced into a given compartment.
DISADVANTAGES
• Drug given by IV route may behave according to single compartment model but
the same drug given by oral route may show 2 compartment behaviour.
• The type of compartment behaviour i.E. Type of compartment model may change
with the route of administration.
TYPES OF COMPARTMENT
1. Central compartment Blood & highly perfused tissues such
as heart, kidney, lungs, liver, etc.
2. Peripheral compartment Poorly per fused tissues such as
fat, bone, etc. MODELS: “OPEN” and “CLOSED” models:
• The term “open” itself mean that, the administered drug dose
is removed from body by an excretory mechanism ( for most
drugs, organs of excretion of drug is kidney)
• If the drug is not removed from the body then model refers as
“closed” model.
⦿ Depending upon whether the compartment
are arranged parallel or in series
,compartments models are divided into two
categories –
◾ Mammillary model
◾ Catenary model
This is the most common compartment used in pharmacokinetics.
dX =
− K Ε X
dt
Elimination phase can be characterized by 3 parameters—
1. Elimination rate constant
2. Elimination half-life
3. Clearance.
The above equation shows that disposition of a drug that follows one-compartment
kinetics is monoexponential.
X = Xo e–KEt
X = Vd C
KE t
log C = log C 0 -
2.303
KE = Ke + Km + Kb + Kl + ......
if a drug is eliminated by urinary excretion and metabolism only, then, the fraction of
drug
excreted unchanged in urine Fe and fraction of drug metabolized Fm can be given as:
Ke Km
Fe = Fm =
KE KE
Elimination Half-Life: t1/2 = 0.693
KE
0.693Vd
t1/2 =
ClT
• Clearance.
Since these parameters are closely related with the physiologic mechanisms in the bo
they are called as primary parameters.
X0 i.v.bolus dose
Vd = =
C0 C0
Clearance is defined as the theoretical volume of body fluid containing drug (i.e. that
fraction of apparent volume of distribution) from which the drug is completely removed
in a given period of time. It is expressed in ml/min or liters/hour.
X0
ClT =
AU C
R
X = 0 (1 − e - K E t )
K E
R0 R0
C= (1−e-KEt ) = (1 −e-KEt )
KEVd ClT
R0 R Infusion rate
Css = = 0 i.e.
K E Vd ClT Clearance
One-Compartment Open Model: Extravascular Administration
dX = dX e v − d X E
dt dt dt
K FX
X= a 0 e-KEt -e-Kat
(Ka - KE )
C=
Ka FX0
Vd(Ka - KE )
e-KEt - e -Ka t
At peak plasma concentration, the rate of absorption equals rate of
elimination i.e. KaXa = KEX
dC = Ka FX0
dt Vd(K a - K E)
- K E e-K t + Ka e-K t
E a
= Zero
KE e -K Et = K e -K at
a
Ka t
log K E - K E t = log K a -
2.303 2.303
2.303 log (K a /K E )
t max =
Ka - KE
F X 0 e - K E t m ax
C m ax =
Vd
Absorption Rate Constant: It can be calculated by the method of residuals. The technique
is also known as feathering, peeling and stripping. It is commonly used in
pharmacokinetics to resolve a multiexponential curve into its individual components. For a
drug that follows one-compartment kinetics and administered e.v., the concentration of
drug in plasma is expressed by a biexponential equation.
C=
Ka F X0
e -K E t - e -K a t
V d (K a - K E )
→
C = A e -K E t
log →C = l o g A -
KEt
2. 30 3
(→
C - C) = C = A e -K a t
Ka t
log C =log A -
2.303
The method involves determination of Ka from percent unabsorbed-time plots and does
not require the assumption of zero- or first-order absorption.
XA = X + X E
X =K V [AUC] t
E E d 0
X = V C + K V [AUC]t
A d E d 0
X = V C + K V [AUC]
A d E d 0
X =K V [A UC ]
A E d 0
X A = V d C + K E V d [AUC] t
0 = C + K E [A U C ] t0
X A K E V d [AU C] K E [A U C ]
0 0
XA 1 − C + K E [AUC] t0
%ARA = - 100 =
1 100
XA K E [AUC] 0
INFLUENCE OF KA AND KE ON CMAX, TMAX AND
AUC
Parameters Influence when KE is Influence when Ka is
affected constant constant
Cmax
4. Volunteers must be instructed to completely empty their bladder while collecting urine samples.
5. Frequent sampling should be done in order to obtain a good curve.
6. During sampling, the exact time and volume of urine excreted should be noted.
7.An individual collection period should not exceed one biological half-life of the drug and ideally should
be considerably less.
8.Urine samples must be collected for at least 7 biological half-lives in order to ensure collection of more
than 99% of excreted drug.
9. Changes in urine pH and urine volume may alter the urinary excretion rate.
*
1. Rate of excretion method, and
2. Sigma-minus method.
Rate of Excretion Method: The rate of urinary drug excretion dXu/dt is proportional
to
the amount of drug in the body X and written as:
dX u
= K eX
dt
According to first-order disposition kinetics, X = Xo e–KEt
dX u
= KeX 0 e -K Et
dt
dXu KEt
log =logKX -
e 0
dt 2.303
Sigma-Minus Method: A disadvantage of rate of excretion method in estimating KE is that
fluctuations in the rate of drug elimination are observed to a high degree and in most
instances, the data are so scattered that an estimate of half-life is difficult. These problems
can be minimized by using the alternative approach called as sigma-minus
method. dX u
= K e X 0 e -K E t
dt
K X
X u = E 0 (1 - e -K E t )
KE
Xu = cumulative amount of drug excreted unchanged in urine at any time t. As time approaches
infinity i.e. after 6 to 7 half-lives, the value e–KE∞ becomes zero and therefore the cumulative amount
excreted at infinite time Xu ∞ can be given by equation
X u = K e X 0
KE
X
u - X u = X u
e - K Et
log (X - X ) = log X - K E t
u u u
2.303
(Xu∞ – Xu) = amount remaining to be excreted
i.e. ARE at any given time.
A semilog plot of ARE versus t yields a straight line with slope -KE/2.303.