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_BASIC PHARMACOKINETICS - CHAPTER 11: Multicompartment model*

_BASIC PHARMACOKINETICS - CHAPTER 11: Multicompartment model*

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Published by: DrHeba on Nov 18, 2007
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`
PHARMACOKINETICS: MAMMILLARY MODELS
 For many drugs, the equilibrium between drug concentrations in different tissues is not achievedrapidly. Thus, one of the assumptions of the one-compartment open model sometimes becomesinvalid. A more complex mammillary open model is often necessary to describe mathematicallythe plasma concentration data (for example) seen after the administration of some drugs. Thesimplest mammillary open model is a two-compartment open model where the drug is bothintroduced into and exits from the central compartment ; for example:
 
Compartment One (X
1
, the central compartment) can be sampled through the blood(or plasma, or serum). It may consist of organs or tissues which, being highly perfused with blood, are in rapid equilibrium distribution with the blood.
 
Compartment Two (X
2
, the peripheral compartment) cannot normally be sampled. Itmay consist of organs or tissues which, being poorly perfused with blood, are in slowequilibrium distribution with the blood.
 
The Body is the sum of both compartments.
1.
 
Intravenous Bolus Administration: Plasma Concentration Data
Recall that for a one-compartment open model, the plasma concentration follows theequation:
( )
0
kT 
Cp Cp e
=
(11.1.1)
i.e., theconcentration of drug in the plasma declines mono-exponentially with time (onestraight line on semi-log paper.)
12
 
 
X
1
X
2
 
21
 
10
 X
0
 
Plasma Concentration vs. Time
1010010000 5 10 15 20 25 30
Time
   P   l  a  s  m  a   C  o  n  c  e  n   t  r  a   t   i  o  n
 
2.
 
Bi-exponential Properties of Two-Compartment Open Model
Following an intravenous bolus injection, the plasma concentration against time profilehas two phases:a.
 
Initial phase - (
α
- phase) b.
 
Terminal phase - (
β
- phase)On semilogarithmic paper (logarithm on the Y axis), the terminal phase is linear,indicating that initial distribution has been completed and that equilibrium has been attained. The terminal half life (T
½
β
) can be measured from the terminal phase.For a two-compartment open model, The plasma concentration follows theequation:
( ) ( )
11
T
Cp Ae Be
α β 
= +
(11.1.2)
i.e., the concentration of drug in the plasma declines bi-exponentially withtime.
2.1 Symbols
i.
 
A
1
and B
1
are intercept constants (m/L
3
)ii.
 
α
and
β
are hybrid rate constants (T
-1
)iii.
 
V
1
is the apparent volume of unchanged drug distribution in compartment1 (L
3
)iv.
 
10
, k 
12
, and k 
21
are the “micro” rate constants (T
-1
)
 
Plasma Concentration vs. Time
1010010000 5 10 15 20 25 30
Time
   P   l  a  s  m  a   C  o  n  c  e  n   t  r  a   t   i  o  n
 Alpha PhaseBeta Phase
 
2.2 Relationships
:
( ) ( ) ( )
( )
21012211012211021
142
k k k k k k k
α 
= + + + + +
(11.1.3)
( ) ( ) ( )
( )
21012211012211021
142
k k k k k k k
 β 
= + + + +
(11.1.4)
( )( )
2111
 D  A
α α β 
=
(11.1.5)
( )( )
2111
 D  B
 β α β 
=
(11.1.6)
011
Cp A B
= +
(11.1.7)
121021
k k
α β 
+ = + +
(11.1.8)
1021
k
αβ 
=
(11.1.9)2.3 Obtaining Pharmacokinetic Parameters by “Feathering”
By convention,
α
>
β
 a.
 
Plot C
 p
against t on semilogarithmic paper  b.
 
Find t
½
from the linear terminal phase: see “IntravenousAdministration,” section A1.4ac.
 
Calculate the terminal hybrid rate constant (
β
); in reality itcontains both distributive (k 
12
and k 
21
) and elimination (k 
10
)factors.
12
ln(2)()
 β 
 β 
=
(11.1.10)
d.
 
Draw a straight line through the linear terminal elimination phaseand extrapolate this line to t = 0. The intercept is equal to B
1
.e.
 
Read extrapolated plasma concentrations
 p

from the plot at timesequal to those given for values of C
 p
which are prior to theterminal phase.f.
 
At each of these times, calculate:
diff 
 p p p
C C
=

(11.1.11)
g.
 
Plot
diff 
 p
against t on semilogarithmic paper. The plot is a“feathered” line and should decline linearly.h.
 
Find the half-life of the plot. It will refer to the initial phase.Calculate,
12
ln(2)()
α 
α 
=
(11.1.12)
i.
 
Measure the intercept of the “feathered” line; it will be equal to A
1
 (note that A
1
 
B
1
, even theoretically). j.
 
Calculate (C
 p
)
o
from Eq. (11.1.7)k.
 
Calculate V
1
by

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