COMPARTMENT MODELLING

Ch-9
261
andthat
OCan be eliminated
from body. Fig. 9.1 shows such
ent model. One-compartment
the
one-compart
open model is
used to descrscribe plasma levels foll generally
wing administration of a single dose
9 of a drug
Compartment Modellino Blood and
Other
Metabolism
Drug Input
Body Tissues Output
(Absorption) (Elimination) Excretion
drug conc entration determined after .
The time course of ts administra Fig. 9.1 Representation of
one-compartment
tion can be satisfactorily explained by assuming the body as a singe open model showing input and output processes.
with first-order disposition Dror
well-mixed compartment In case
dugs, two or more body compartments may he nending upon the rate oI input, several one-compartment open
of other
describe mathematically
the data collected. ated to models can be defined:
One-compartment open model, i.v. bolus administration.
ONE-COMPARTMENT OPEN MODEL One-compartment open model, continuous i.v. infusion.
(Instantaneous Distribution Model) One-compartment open model, e.v. administration, zero-order
The one-compartment open model is the simplest model. Owino absorption.
its simplicity, it is based on following assumptions to One-compartment open model, e.v. administration, first-order
1. The body is considered as a single, kinetically homogeneous unit
y a b s o r p t i o n .
that has no barriers to the movement of drug. Ope-Compartment Open Model
2. Final distribution equilibrium between the drug in plasma and /Intravenous Bolus Administration
other body fluids (i.e. mixing) is attained instantaneously and When a drug that distributes rapidly in the body is given in the form
This model thus applies only to those
maintained at all times.
drugs that distribute rapidly throughout the body.
of a rapid intravenous injection (i.e. i.v. bolus or slug), it takes about one
of
to three minutes for complete circulation and therefore the rate
3. Drugs move dynamically, in (absorption) and out (elimination) absorption is neglected in calculations. The model can be depicted as
of this compartment. follows:
4. Elimination is a first-order (monoexponential) process with first
order rate constant.
Blood and Other
Body Tissues
-
5. Rate of input (absorption) > rate of output (elimination). presentation to the body IS:
6. The anatomical he general expression for rate of drug
reference compartment is plasma a
tration of drug in centration
in all
plasma
is presentative of drug
ntration
dX
in (availability) -Rate out (elimination) 9.1)
body tissues i.e. any change in plasma drug coi Rate
dt
reflects a proportional change in drug concentration throughou
the body. Ce rate in or absorption is absent, the equation becomes
However, the model does not assume that the drug concent
plasma is
equal to that in other pen
i n d i c a t e s
dX=-Rate out (9.2)
hat the body tissues. The term dt
input (availability) and output
idirectima
(elimination) ar
 M E N T MODELLING
OMPARTM
BIOPHARMACEUTICS AND HARMACOKINET 263
parameter that permits the
nacokinetic
harmacokine use of plasma drug
kinetice
place of amount of
place drug in the
body. The
elimination
follows first-order
then n t r a t i o n

in
equation 9.6
If the rate out or become
therctore
n c
dX-KEX logC log Co-Et
=
2.303 (9.3)
dt 9.3
elimination rate
constant, and = plasma drug concentration immediately after i.v. injection.
first-order
where KE =
at any time t remain
= amount of drug
in the boay
ining Equation
w h e r e
9.8 is that of a straight line and indicates that a
9.8
to be eliminated.
i plot of log C versus t will be linear with y-intercept log
is being lost from the
semilogarith
elimination rate constan is directly obtained from the slope of
Negative sign
indicates that the drug body 9.2b). It
has units of Thus, a linear plot is easier to
Parameters -IV Bolus the line (Fig.
mathematically than a curve which in this case will be obtained
Pharmacokinetic
the
Estimation of handle m a t h
handle t Of CC versus t on regular (Cartesian) graph paper (Fig. 9.2a).
Administration kinetics and ad plot of
administered
a
one-compartment from
that follows
For a drug decline in plasmna drug concentration i log
as rapid
i.v. injection,. the not due to
die,only
elimination
from the body (and
of drugelimination phase. Elimination phase ution), (a) Regular
(Cartesian) Plot (b) Semilogarithmic Plot
due to
called as mination phase ca
the phase being
characterized by 3 parameters-
Log slope =
constant
1. Elimination
rate 2.303
2 Elimination half-life
3. Clearance
log C
Elimination Rate Constant: Integration of equation 9.3 yields:
In X =In X, -
K t
9.4)
Time t
of drug at time t = zero
where. X = amount
of a drug that follows one-compartment
ie. the initial amount of drug injected.
Fig. 9.2 (a) Cartesian plot
i.v. injection, and (b) Semilogarithmic
kinetics and given by rapid
Equation 9.4 can also be written in the exponential form as:
in a one-compartment model.
plot for the rate of elimination
X =Xo e-KEt (9.5) C versus t
Thus, Co, K (and t) can be readily obtained from log
the sum of
The above equation shows that disposition of a drug that follows The elimination or removal of drug from the body is
graph. excretion, pulmonary excretion,
one-compartment kinetics is monoexponential. urinary excretion, metabolism, biliary additive prop-
and other mechanisms involved
therein. Thus, K is an
Transforming equation 9.4 into common logarithms (log base 10),
we
better called as
of these processes and
get: erty of rate constants for each
overall elimination rate constant.
log X log Xo
= -
KEt (9.6) (9.9)
2.303
Kp Ke + Km + Ky + K t . .
Since it is difficult to determine directly the amount of drug in tne can be evaluated
particular route
ne fraction of drug eliminated by
a
For
body X, advantage is taken of the fact that a constant relationship exb the number of rate constants involved and their
values are known.
berween drug concentration in plasma C (easily measurable) and X; tnus metabolism
excretion and
by urinary
9.7) ple, if a drug is eliminated excreted unchanged in
urine Fe and
X = VaC nen, the fraction of drug
HCon of drug metabolized Fm can be given as
where, Va= proportionality constant popularly known as the
apparent volume of distribution.
 (OMPARTME
T NM
T
MOOD
DEEL
LLING
BIOPHARMACEUTICs AND PHARMACOKINETICS
264
i.v.bolus dose
F.
K
KE
Co
9.10a n 9.14 can only be used for drugs that obey one-compartment
quala because the only
be estimated when
an
distribution
Fn This is
KE kinctrcs
equiibrium is achieve etween drug in plasma and that in tissues and
(9.106) such an cquilibri
brium is establisished instantaneously for a drug that follows
Elimination Haif-Life: Aiso called as biological half.Jie,. ompartment kine netics. A more
general, more useful
oldest and the best known
of all pharmacokinetic parameters the cntal method that can be applied to many compartment
and
the most important characteristic of a de
ncompartme
o n e
once considered as
ay the Vg is:
estimating
defined as the time taken for
the amount of drug in the body
as
i fels for
i.v. bolus,
plasma concentration to decline by one-half or 50 its initial value.ll as drugs
given
as
For
Half-life is related to Xo
is expressed in hours or minutes. elin
constant by the following equation: rate Va(area) K AUC (9.15a)
0.693 nistered extravascularly (e.v.),
KE
For d r u g s a d m i n i s
(9.11)
Elimination haif-life can be readily obtained from the graph of log Va (area)K FXo
AUC 9.15b)
versus t as shown in Fig 9.2.
Today. increased physiological understanding of pharmacokineties X= dose
administered, and F fraction =
of drug absorbed into
one ie. complete
ore
circulation. F is equal to
shows that haif-life is a secondary parameter that depends upon the the systemic
is administered intravenously.
primary parameters clearance and apparent volume of distribution. availability when the drug
according to following equation: when applies elimination rate
Difficulties arise one
Clearance : in an anatomical/
half-life pharmacokinetic parameters
0.693 V constant and
as
of drug elimination mechanisms.
measure
(9.12) context and as a
Cl physiological is use
valuable alternative approach for such applications
A much more is
Apparent Voiume of Distribution : The two separate and independ- to characterize drug disposition. Clearance
of clearance parameters
drug applications and useful
is
ent pharmacokinetic characteristics of a drug are- in clinical
the most important parameter the whole
which drug is eliminated by
evaluating the mechanism by
a
1. Apparent volume of distribution, and in
organism or by a particular organ.
2. Clearance. concentration with
Just as Vd is needed to relate plasma drug
Since these parameters are closely related with the physiological clearance is a parameter that
relates plasma
ämount of drug in the body, to follow-
mechanisms in the body, they are called as primary parameters. elimination according
rate of drug
volume of distribution:
urug concentration with the
Modification of equation 9.7 defines apparent ing equation:
Rate of elimination
Amount ofdrugin the body X 9.16)
V =
V,
Plasma drug concentration
(9.13) Clearancee =
Plasma drug concentration
V is a measure of the extent of distribution of drug and is expressed dX (9.17)
in litres. The best and the simplest way of estimating Va of a drug b
na Or Cl=d
administering it by rapid i.v. injection, determining the resulting la C
concentration immediately and using the following equation:
 266 BIOPHARMACEUTICS ANDND PHPHARMACOKINET COMPARTMENT MODELLI ING
Clearance is defined as the theoretical volume ot t 261
of
of body fluid
that fraction of apparent volume
C h - 9
ing drug (i.e.
which drug
the is completely removed in
given peri d of time a distributi contai Cl= X
C (9.19)
expressed in ml/min or litres/hour. Clearance is usually
as blood clearance (Clp). plasma clearance (CI) orcurther (fron equation 9.13), the equation can be
pon the ba Asedenedon
9.19
free drug concentration (ClL), dependine Since

X = Va
tion C measured for the right side of the equation 9.17
C Total Body Clearance : Elimination of
concentra writtena s
Cl KE V (9.2
in
a
drug fro ans ccan
a n be written for renal and hepatic clearances as:
involves processes occurrin kidney, liver, lungs and the equations
Clearance at an individual organ level other elimis
is body Paralle
organs. called as organ Cl K, V (9.20b)
clearance. It can be estimated by dividing the rate of
elim
each organ with the concentration of drug presented to
it. ination by
Thus. Clu=K, V (9.200)
Renal Clearance
Ke = 0.693/t4 (from equation 9.11), clearance can be related to
ind equation:
ClR
Rate of elimination by kidney half-life by
the following
C 0.693 Va
(9.18a Cl =
(9.21)
Hepatic Clearance
can be Clp Cly
writen for and in which cases the
Rate of elimination by liver Identical equations
ClH excretion half-life for unchanged drug
and metabolism
C (9.18b) t will be urinary Equation 9.21 shows that
as Cl decreases, as in
Other Organ Clearance
half-life respectively. of the drug
As the ClT takes into
increases.
renal insufficiency, th or oedematous condition
will
in Va as in obesity
Rate of elimination by other organs account Vd, changes
Clohers C (9.18c)
reflect changes in ClT.
method of computing total clearance for a
The noncompartmental
The total body clearance, ClT, also called as total kinetics is:
follows one-compartment
systemic clear drug that
ance, is additive property of individual organ clearances. Hence,
an
For drugs given as i.v. bolus
Total Systemic Clearance X
0 (9.22a)
Cl Cl +Clu +Clhers (9.18d)
Cl AUC
Because of the
additivity of clearance, the relative contribution b For drugs given e.v.
any organ in eliminating a drug be casily calculated.
all organs other than
can
Clearance Dy (9.22b)
ance
kidneys is sometimes known
nonrena as Cl AUC
ClNR It is the difference
between total clearance a may de
clearance. renal clearance ClR
drug given by i.v. bolus, the excretea
According
a total amount of unchanged drug
to an earlier definition
(equation 9.17), d c a b y determining the
in
urine, X," and AUC.
dX (9.17)1 (9.23)
Cl ClR
C
Substituting dX/dt =
KpX from equation 9.3 in above equatio
we
 268 BIOPHARMACEUTICS AND
sO PH
PHARMACOKINET RTMENT
T M E N T

MOns
MODELLING
269
(OMPAR
Organ Clearance : The best way of understandi. Clearance : For certain drugs, the nonrenal clearance cann tbe
level. Such a
physiological ding cleara h9
to hepatic
clearanc
rance ClH It is given
individual organ
the influence of patho proach is arance Heas
assumcd
equal
as:
in predicting and evaluating
binding, enzyme activity,
etc. on drug eliminatior pathology, bloodadvantage ClH Cl-ClR 9.30)
the rate of elimination
can be written as:
At an
Jow,PD
organ llee ve cquation

rallel
parallel
to
to equation 9.28 can also be written for
e
hepatic
Rate of elimination Rate of presentation An
to the organ
Rate of exit clearance: Cl = Qn ER
by an organ from the (9.31)
organ (9.24 blood flow (about 1.5 litres/min), and
Rate of presenta- hepatic blc
tion (input)
= Organ blood flow x Entering Ou
=
hepatic
extraction ratio.
= Q Cin
concentration ere,
ERH
=
hepatic
clearance of drugs can be divided into two groups
9.25 The hepatic cle
hepatic blood flo rate-limited clearance, and
Rate of exit with
= Organ blood flow Exiting 1. Drugs
with intrinsic capacity-limited clearance
(output) concentration 2. Drugs
Rate-Limited Clearance: When
Q Cout 9.26 Hepatic
Blood low ERH is
1. its maximum value i.e. hepatic blood flow. In such
Substitution of equations 9.25 and 9.26 in equation 9.24
approaches
ClH clearance is said to be perfusion rate-limited or
elds: one,
tion, hepatic
Rate of elimination =Q Cin a situa
Alteration in hepatic blood flow significantly affects
Q Cout lidocaine, etc.
of dru with high ERH e.g. propranolol,
f l o w - d e p e n d e n t .
(alsocalled as Rate of extraction) = Q (Cin - Q Cu) elimination
from the blood as rapidly as they are presented
9.27) the
drugs are
removed
is so
hepatic metabolism). Indocyanine green
Such
Division of above equation by concentration of drug that to the liver (high first-passhuman is often used
enters the hver that its clearance
as
organ of elimination Cin yields an expression for clearance of drug hv rapidly eliminated
by the extraction is
blood flow rate. First-pass hepatic
the organ under consideration. Thus:
an indicator of hepatic in systemic circulation
there is lack of unchanged drug
Suspected when Maximum oral availability F
for such drugs
Rate of extraction
Cin
organ QCin Cout= (9.28)
after oral
administration.
be computed from equation
9.29. An extension of
the same equa-
Cin can
method of estimating F:
tion is the noncompartmental
where, ER = (Cin Cout/Cin is called as extraction ratio. It has no
units and its value ranges from zero (no
elimination) to one (complete F=1-ERH AUCo (9.32)
elimination). Based on ER values, drugs can be classified into 3 groups AUCi
1. Drugs with high ER
(above 0.7), TABLE 9.1
2. Drugs with intermediate ER on Total
(between 0.7 to 0.3), and and Protein Binding
Influence of Blood Flow Rate
3. Drugs with low ER with Low and ER Values
(below 0.3). Clearance of Drugs with High
ER is Clearance due to
an index of how efficiently the eliminating organ clears n Changes in
Total
blood jlowing through it of drug. Binding
For
example, an ER of 0.6 teis Blood Binding
60% of the blood
flowing through the organ will be cleared Drugs with Blood
of
drug. The fraction of drug that compietcay
tne rgan
Flow Flow
expressed as: escapes removal by 5 No change
No change
High ER (above 0.7)
F 1 ER (9.29) Low ER (below No change
0.3) No change
wnere, F systemic availability when the eliminating organ liver.
wnere, T= increase, and= decrease
 BIOPHAR
RMACEUTICS AND AARMACOKINETIE PARTMENT MODELILING
270 (MPAR 271
hepatic blood flow has verv li tle or no antibiotics, theophylline, procainamide, etc.) i admin-
antibios
On the contrary,
by i.v.
v e r a l
(zero-order) infusion. In contrast to the
low ERy e.g. theophylline. For such drugs.
Se
rate
with low
drugs with
nstant
whatever l infusion of an i.v. bolus (few seconds), the duration of
e x a n p l e ,
tration of drug present
nt the D
in the blo0d perfuses liver, is
is more than mcen
eliminate (low first-pass enatic
ort duration
is usually uch longer than the half-life of the
liver can
metabolism).
extended to the influence of blood flow o
wh
Similar dis the
c o n s t a n l r a l e
te
infusion
i n f u s i o n
sion can be
illustrated in Table 9.1. Hepatic clearaal clearan infusion of drugs include
drugs. This is drug
aos of zero-order
high ER independent of protein binding.
is
with I.aseof
f control of rate of infusion to fit individual patient needs.
2. Intrinsic Capacity Clearance: Denoted as Cl luctuating maxima and minima (peak and
2. Prevents fluc valley)
as the inherent abilitN of an organ to irreversibly remove
bly remove a drug lefine plasma level.
This is desired especially when the drug has a
absence flow limitation. lt depends, in this case
of any case, upon in narrow therapeutic index.
the
enzyme activity. Drugs with low ERp and with elimination hepai and nutrients can be conveniently ad-
rimarily by drugs, electrolytes
metabolism are greatly affected by changes in
enzyme
activity.
Other
multaneously by the same infusio line in critically
mited, e.g. theophyHepaic
clearance of such drugs is said to be capacity-limited ministered
The t of such drugs shows great intersubject ill patients.
variability.
clearance of drugs with low ER is independent of blood Hepalic can be represented
as follows:
flow The model
sensitive to changes in protein binding. bul
Blood and Other
Ro Elimination
The hepatic and renal extraction ratios of some drugs and
metabolite Drug zero-order Body Tissues
are given in Table 9.2. infusion rate
TABLE 9.2 infusion, the rate of change in the amount of drug
At any time during
difference between the zero-order rate of drug
Hepatic and Renal Extraction Ratio dX/dt is the
in the body, of elimination, -KX:
of Some Drugs and Metabolites first-order rate
infusion Ro and
Extraction Ratio
X (9.33)
High Intermediate Low dt
of above equation yields:
Hepatic Extraction Propranolol Aspirin Diazepam Integration and rearrangement
Lidocaine Codeine Phenobarbital
Nitroglycerine Nortriptyline Phenytoin X=1-e-KEl) (9.34)
Morphine Quinidine Procainamide KE
Isoprenaline Theophylline be transformed into
concen-
Since X = Va C, the equation 9.34
can
Renal Extraction Some penicillins Some penicillins Digoxin tration terms as follows:
Hippuric acid Procainamide Furosemide
(1-e-KEt) Ko(1-e-KE') (9.35)
Several sulphates Cimetidine Atenolol
=
Several glucuronides Tetracycline C ClT
KEVa in the body
infusion, the amount of drug amount
One-Compartment Open Model n e start of constant rate As time passes,
the oof
Intravenous Infusion a n d hence, there is no elimination. than the rate
drug in the body rises gradualy (elimination rate less equals the ratee
Rapid i.v. injection is unsuitable when the drug has poter
infusioni
infusion) until point after which the rate of elimination
approaches a
con-
precipitate toxicity or when
maintenance of a stable co
ration or of infusion i.e. in plasma
entration of drug equilibrium (Fig
amount of
drug in the body is desired. In such a drug Called as steady-state, plateau orinfusion
situau 9.3)
 272 BIOPHARMACEUTICS AND PHAR Ch-9 COMPARTMENT MODELLING
273
Infusion rate 2R OKINETS T r a n s f o r m i n g

into log forn the equation becomes:

log -Kgt
Infusion stopped 2.303 (9.40)
-Infusion rate R when plotted on of(Css-C)/Css versus t results in a straight line with
2.303 (Fig. 9.4).
A s e m i l o g
a
semilog graph, yields slope -Ke/2
a
straight line with
slope K /2.303
-
-
Infusion time =T
**************-
Time
slope -KE
2.303
Fig. 9.3 Plasma concentration-time profile for a drue ven
by constant rate i.v. infusion (the two curves indicate differ
ent infusion rates Ro and 2R, for the same drug)
At steady-state, the rate of change in amount of drug in the 1
zero, hence, the equation 9.33 becomes: body iv
from infusion data upto steady-state
Eio, 9.4
Semilog plot to compute Kg
Zero Ro- KpXs reach steady-state concentration is dependent upon the
The time to
and not infusion rate. An increase in infusion rate
or KEX =Ro elimination half-life
9.36 increase the plasma
concentration attained at steady-state
will merely of half-lives passed since the start of
Transforming to concentration terms and rearranging the n is the number
equation: CFig. 9.3). If
9.38 can be written as:
infusion (Utiz), equation
Ro oie nfusionrate
CK ClT
CK,V, Clearance (9.37) C-C1-(12" (9.4.)
sum of Cs at
where, Xs and Css are amount of drug in the body and concentration of at the end of each t, is the
The percent of Css achieved
drug in plasma at steady-state respectively. The value of K (and hence after a given ta
previous th and the concentration of drug remaining
t)can be obtained from the slope of straight line obtained aftera (Table 9.3).
semilogarithmic plot (log C versus t) of the plasma concentration-time TABLE 9.3
data gathered from the time when infusion is given ty
stopped (Fig. 9.3). Alter Per cent of Css Attained at the End of a
natively, Kg can be calculated from the data collected during infusion to
steady-state as follows:
% Css Achieved
Half-life % Remaining
Substituting RJClT =
Css from equation 9.37 in equation 9.) wo
50 50
75
get: 50
25
25 87.5
12.5
(9.38) 75
C=Cs (1-e-kE) 12.5
6.25
93.75
4 6.25 87.5
Rearrangement yields: 93.75
3.125
96.875
3.125 98.437
1.562
CC (9.39)
. 562
0.781

96.875
98.437
0.781
99.218
 Amount of drug in the body

(O

E
 apio-1Siy
Japio-0132

log ARA

apio-1siy4
apio-01az

Plasma Drug Concentration

Absorption phase
3
a s e y du o y d i o s q ei s o
 COMPARTMENT MODEI
MODELLINNG
BIOPHARMACEUTIcS AND
ND PHAB
PHARMACOKINETE
278
The rate of drug
absorption, as in the ase of several
Ch-9
dC Va(K -KE)
K,FXoKgeEl +K,a"|=
amountmtrol ed dn
is c o n s t a n t
and continues until he Zero
(9.50)
deliver systems, is depleted. AIl eane dt
site (e.g. GIT) of drug
the absorption for constant rate
ons that explain the above equation become
c o n c e n t r a t i o n - t i m e profile i.v. nplifying,
plasma infusi Nain the
this model. are KEeE= K, eKat
applicable to a (9.51)
First-Order Absorption Model -
Extravascular A. .
logarithn form,
orptionstratproton
Converting to
For a drug
that enters the body by a first-order
gets
distributed
is eliminated by
in the
a

body according
first-order process, the ne-compartment
modei ea kinetics an
be depicte
log KE- E
2.303
=log K, -
2.303 (9.52)
follows:
Rearrangement of above equation yields:
where t is tmax
Blood and Other
2.303 log (K,/K)
Drug at
e.v.Ssite first-order
absorption
Body Tissues
Elimination max
Ka-KE 9.53)
u a t i o n shows that
as Ka becomes
The differential form of
the equation 9.46a is: The quation
above eq larger than Ke. tmax
becomes smaller
Kp increases much faster than log KK.
-
dX obtained by substituting equation 9.53 in equation 9.49.
KXa
dt
-KgX max can be
expression for the same is:
9.47 However, a simpler
V/
where, Ka = first-order absorption rate constant, and
A0-KE max
X = amount of drug at the absorption site Cmax (9.54)
remaining to be absorbed i.e. ARA.
shown that at Cmax» when Ka =
Ke, tmax =
1/Kg. Hence,
Integration of equation 947 yields: It has been
further reduces to:
equation
the above
X- K,FKo -KEt--Ka Cmax -10.37FX (9.55)
(Ka-KE) (9.48) Va
Transforming into concentration terms, the equation becomes: Since FXoVa represents C%
following i.v. bolus, the maximum plasma
is 37% of
attained after e.v. administration just
concentration that can be
in the same dose. If
C CK,FXoKK|
Va(K-KE) (9.49)
the maximum level
attainable with i.v. bolus
bioavailability is less than
100%, still lower
concentration will be at-
tained. from
where F fraction of drug absorbed systemically after administa e.v.
Elimination Rate Constant
This parameter can be computed
drugs
tion. Atypical plasma concentration-time profile of drug administered
e.v. is shown in Fig. 9.7.
a
the elinunation phase of the plasma level time profile.
For most
the elimi-
greater than
administered e.v.,absorption rate is significantly era' approaches
one can say that
Assessment of Pharmacokinetic Parameters Extravascular auon rate i.e. Kat >> KEt. Hence, absorption is
e-Kkel. At such a stage, when
Administration erO much faster than does
concentration is dependent only
on
complete, the change in plasma
Cmax and tmax : At peak plasma concentration, the rate of
absopption elhmination rate and equation 9.49 reduces
to:
cquals rate of elimination i.e. K,X, KpX and the rate of cnan
=
plasma drug concentration dC/dt =zero. This rate can be oDtaine by
differentiating equation 9.49.
 sD PHARM.
BIOPHARMACEUTICS AND PHARMACOKINETI pARTMENT
n9 COMPART
MODELLING
283
log KFMo
C
K FXo-Kgt log A -
Va(Ka-KE back extrapolated terminal
form, the equation becomes. portion of curve (log C values)
Transforming into log
K FXo_ KEt true plasma concentration
log C=log Va(Ka-Kp) 2.303 values (log C values)
versus t yields a straight line with
951 residual cure (log C, values)
A plot of log C
be computed from K). Ke slope -Kg/2.3
half-life can then
can
also be
from urinary excretion data (see the section on urinary estima
excretion
slope -
Rate Constant : It can be calculated by
the
data) 2.303
Absorption
feathering, method of
O r T U
also known as
residuals. The technique is
It is commonly used
in pharmacokinetic peeling
to and slope
stripping. resolve a 2.303
multiexponential curve into its individ components. For
a drug that lag time
follows one-compartment
kineticS and administered e.v., the
tion of drug in plasma is expressed by
a i biexponential equation ncentra-
94
C K,FX-KEt --Kat
Va(K-KE)
9.8 Plasma
single dose

concentration-time
of a
profile after
The biexponential curve has been
drug.
oral administra
9.49) tion of a
into its two
components-absorption and elimination.
resolved
If K,FXNa(Ka - K) = A, a hybrid constant, then:
of true plasma concentration values i.e. equation 9.58
Subtraction
plasma concentration values i.e. equation 9.59
C AeE Aeat the extrapolated
-
9.58) fm
from
of residual
concentration values C
a series
During the elimination phase, when absorption is almost over, K. > vields
C-C)=C, =A eKat (9.61)
KE and the value of second exponential eAa approaches zero wherea
the first exponential ehE retains some finite value. At this time, the
the equation is:
equation 9.58 reduces to: In log form,
Kat 9.62)
C=A Kt 9.59) logC1ogA 2.303
In log form, the above e,juation is: a straight line
with slope -K/2.303
A plot of log Cy versus t yields can then be
Absorption half-life
and y-intercept log A (Fig. 9.8). Thus, the method of
log =log AA--KEt
logC C=log (9.60) computed from K using the relation 0.693/K
2.303 rEsiduals enables resolution of the biexponential plasma
level-time curve
best when
The technique works
where C represents the back
extrapolated plasma curve win a mto its two exponential components. In some
values. A plot of log C versus t yields a biexponential concentratio is large (K/K
2 3).
ne difference between Ka and K is
of the same drug very
large,
terminal linear phase having slope -Kp/2.303 (Fig. 9.8). Back extrapoi* stances, the K obtained after i.v. bolus
tion of obtained by the
method of residuals (e.g.
this straight line to time
yields y-intercept equal to log n:
zero larger than the Ka estimates Ka and not
naline) and if K/K, 23, the terminal slope is
and not Ka his
E the slope of residual line gives Kg
Wnereas
log % ARAA J

960)
 BIOPHARMACEUTICS AND PHARMA.
P A R T M E N M O D E L L I N G
284 285
h - 9 COMPA
when there is lack of
useful
sufficiently
line whose slope is -Ka/2.303 (Fig.9.9). 1f
straightline. then absorption iS zero-order.
a
regular plot of the MACOKINEe .
The

ethod
analytica techniques to
is
sure concentration of drugs
sensitive
in plasma
Ka can similarly be estimated from urinary exe same is with accuracy.
invasive and therefore bette subject compli-
relevant section). The biggest
disadvantage of retion data 2 . T h e m e t h o d
Wagr
ner-Nel son (see the
a n c e i s a s s u r e d .
is that it applies only to drugs with one-compartm od is more convenie since it involves collection of
ment character
Problem arises when drugathat obeys
one-compartme methot mples in
c o m p a r i s o r to drawing of blood
periodicaily.
ninistration shows multicompartmentcharacteristicodel af
i.v. injection
urine
sensiti
ytical method is required for determining
les
Effect of K, and Ke on Cmax: tmax and AUc A
urine drug
oncentration as compared to plasma concentrations.
conce
4.
inig concentrations are low, assaying of larger sample
A summary of the influence of changes in I furine drug
K, at con.
Kg at constant K on and AUC of a
Cmax. tmax nt Ke and is relatively
easy.
drug administered volumes
shown in Table 9.4.
istered e.x.is First-order

nination, excretion and absorption

unchanged can be computed from such
excrete:

rate constants
fraction
TABLE 9.4 extra-renal excretion rate con-
First-order metabolism or
Influence of Ka and Ke on
Cmax tmax calculated subsequently from the difference
and AUC nt can also be
K) = Km
Parameters Influence when K is constant
nfluence when K. is cor
(KE of bioavailability, both absolute and rela-
affected Smaller Ka Larger Ka Smaller KE Constan Direct
m e a s u r e m e n t
without the necessity of fitting the data to a
Larger Kg tive,
Ive is possible
Cmax mathematical model.
max Long Short with plasma level-time data, it can also be used
Long Short 7 When coupled
AUC clearance of unchanged drug according to
No Change No Change toestimate renal
following equation:
where, T = increase and = decrease.
Total amount of drug excreted unchanged
Apparent Volume ofDistribution and Clearance : For a (9.70)
follows one-compartment kinetics after e.v. drug that ClR Area under the plasma level time curve
can be
administration, Va and Ch
computed from equation 9.15b and 9.22b
respectively where F is is known, total systemic clearance and nonrenal clearance can
the fraction absorbed into the If Va
systemic circulation. also be calculated.
and ClT from urine data aione.
FXo One cannot, however, compute Vd
Va excretion data is not an accurate
K AUC 9.15b) One must also remember that urinary
the data can be employed
substitute for the plasma level data. At best,
Moreover, if the
as a rough estimate of the pharmacokinetic parameters.
Cl= FXo
AUC (9.22b)
release or if the drug has
drug product provides a very slow drug low urinary drug concentration
a very
long biological half-life, the resulting
the latter case, i.e. for
be assessed with accuracy. In
ay de to0 dilute to for several days to
URINARY EXCRETION DATA ugs with long ty, urine may have to be collected
(Disposition Viewed from Urine
only)
account for total drug excreted.
In the absence of plasma
be obtained from urine data
level-time data, useful information can ustill
The method
has several regarding elimination kinetics a
drug. o
system: advantages in the
analysis of cokinetic
a
pharna
 286 BIOPHARMACEUTICS AND PUA cn-9 COMPARTMEN
ANRMACOXNET
eaMPARTMENT MODELLING
287
Criteria for Obtaining Valid Urinary Excretion Data TABLE 9.5
of drug
1. A significant
amount
must be
excreted u r i n a r yE X c r e t i o n D a t Data following i.v. Bolus of 100 mg of a
Drug
urine (at least 10%).
method
unchan in Treatment of data
2. The analytical must be specific for
O h s e r v a t i o n s
the Conc. Urine Mid- Amount Excret. Cumul.
metabolites should not interfere.
unchang Time
ume

Vol
of coll
Amount
point excreted rate amount remain-
Water-loading should be done by ection of in time (mg/H)
taking 400 m
unch- excre-
of ing to
fasting ovenight, to promote diuresis and of water S a m -
wine
anged
inter urine interval ted be
enable collectionalteor
urine
ollec- drug val collec- dX,/dt
sufficient urine samples. coll- Aexcreted
dt (or tion orAX,
Iion
ected in urine mg) (X
Ar) * mg)
4. Before administration of drug, the bladder (mcg X)
(hrs)
(ml)
must
be empliel
completely after 1 hour from ter-loading and the urine ml) (mg)
taken as blank. The drug shoul then be sampje 66.7
200 ml of water and should be
hourly intervals for the next 4 hours.
followed by administsered with
200 ml
140 250 2 1 35.0 17.5 35.0 31.7
0-2
100 2 3 15.0 7.5 50.0 16.7
5, Volunteers must be instructed to completely empty theie 150
2-4
while collecting urine samples. bladidkr 4-6 90 80 2 5 7.2 3.6 57.2 9.5
3
6. Frequent sampling should be done in order to 20 2 7 4.0 2.0 61.2 5.5
curve.
obtain a good
obtain
6-8 200
8-12 310 10 4 10 3.1 0.8 64.3 2.4
7. During sampling, the exact time and volume of urine
should be noted.
urine excreled 6 12-24 600 04 12 18 2.4 0.2 [66.7]
8. An individual collection period should not exceed
one biologinl
half-life of the drug and ideally should be
considerably less.
9. Urine samples must be collected for at least 7 biological halt.
lives in order to ensure collection of than 99%more
TU
of excreted from Urinary Excretion Data
drug. Determination of Ke can be
10. Changes in urine pH and urine volume The first-order
elimination (and excretion) rate constants
may alter the urinary data by two methods:
excretion rate. computed from urine
method
The urine data 1. Rate of excretion
can be set as shown in the Table 9.5. Observations 2. Sigma-minus method.
include times of urine collection, volumes collected and
concentration of The rate of urinary drug
excretion
unchanged drug in each sample. These data are treated to derive further Rate of Excretion Method: X and written
amount of drug in the body
information. dX/dt is proportional to the
as
(9.71)
dXuKX
dt
According to
where Ke = first-order urinary excretion rate constant.
Substituting
rst-order disposition kinetics, X =Xo eKel (equation 9.5).
it in above
equation yields:
dXu-KXXo5eKEt (9.72)
dt
 288 BIOPHARMACEUTI AND PHARMACOKINETC
9 RTMENT MODELLING
COMPARTA
where X 289
dose administered (1.V. bolus). Upon transforn
ransformation to
=
rlier equation:
form the equation becomes: From an carli
dXu -K.XeE
log dXu log Keo2.303
KEt dt (9.72)
dt
of equation 9.72 yields:
The above equation states that a semilog plot of rate
(9.7 Integration
versus time yields a straight line with slope -Kp/2.3 of excreli
x, =EO(1-e-Ket
must therefore be remembered that an e: the slope of such .10). 1 KE (9.74)
versus plot related
time elimination rate constant
is to
Kpxcretion rlte
excretion rate constant Ke. The excretion rate constant can and not =

amulative amount of drug excreted unchanged in urine at

cumulative
o Xu infinity i.e. after 6 to 7 half-lives, the
Eliminationn half-life andbe
obtainel
ere approaches
from the y-intercept (log Ke X). As time
time t.
hecomes zero and therefore the cumulative amount excreted
then be n any
elimination rate constant can computed from Kp and rena value e E
An advantage of excretion rate method is that for drugs ho.
Ke infinite
time Xy can be given by equation:
half-lives, urine may be collected for only 3 to 4 half-lives ving long
at
X
there is no need to collect all urine samples since
collection of any Moreove KE (9.75)
consecutive urine samples yield points
on the rate plot from
line be constructed. Sutbstitution of equation
9./5 in equation 9.74 and rearrangement
straight can
yields:
X X =
X ekE (9.7
log KXo
Converting to logarithms, we get:
log (Xu X,) =log Xu KEt
2.303
(9.77)
log
dt slope
2.303
where(X -
Xu) = amount remaining to be excreted i.e. ARE at any
of ARE versus t yields a straight line with
given time. A semilog plot
also called as ARE plot
slope -Kp/2.303. The method is, therefore,
method. A disadvantage of this method is
that total urine collection has
carried out until no unchanged drug can
be detected in the urine
to be
tedious for drugs having long u
(midpoint time of urine collection) 1.e.upto 7 half-lives, which may be
from the urinary excretion
The equations until now for computing K^
Fig. 9.10 Semilog plot of excretion rate versus
mid model and given as 1.v.
point time of urine collection period for computing ata apply to a drug that fits one-compartment
constant rate i.v.
infusion can be
elimination rate constant after i.v.
bolus administration. OUs. Similarly, data obtained during
USed to evaluate the elimination rate constant. The equation
that de-
Sigma-Minus Method: A disadvantage of rate of excretion tho when administered
of unchanged drug
urinary excretion rate
in estumating Ke is that fluctuations in the rate of drug elimination e as i.v. infusion. Inus
LV. bolus also applies when it is administered
observed to a high
that an estimate of
degree and in most instances, the data are so se tered
9.71)
mized by
half-life is difficult. These problems can be min
using the alternative approach called as
sigma-minus e
dXu=KX
dt X is
For given as i.v. infusion, the amount of drug in the body
gven u g
given
by equation (described earlier)
 290 BIOPHARMACEUTICS AND PHARM h9 COMPARTMENT
MPARTMENT MODELLING
93
X Ro (1-e-KEt
KE
CORINETE F o r

a drug given
and absorbed by a first-order process, X
Substitution of equation 9.34 in equation 9.71 an.
71 and integration 934
givena s
K,FXoKEK
K-KE) (9.48)
same yields: ion of
the
KRoKK0KRo-e-KEl)
KE Kp2
Substitution o f
same yields:

of equation 9.48 in equation 9.71 and integration of the

K K , F X o | L , eKEt
When the drug has been infused for a period 978 KgeKat
long X KE Ka (KE-K,) K, (KE -K,) (9.80)
steady-state in the plasma, the term
equation reduces to:
-KEl
approaches zeroenough
and
to atin
the above to
the equation 9.80 reduces
infinity,
At time
Xu KeRot KRo x=eFXo
KE KgE KE (9.81)
9.79)
A regular plot of cumulative amount of
drug excreted X. of equation 9.81 in equation 9.80 and subsequent rear-
yields a curvilinear plot the linear portion of which has a slone kversus
.
Substitution
Extrapolation of linear segment to time axXis yields RKE
x-intercept cqual to
rangement yields:
1/KE since when X, = 0, t = 1/K (Fig. 9.11).
= (K,ekE_-Kgeka (9.82)
ARE
=(X -Xu)=KK
(KE-Ka
in a biexponential curve
of (Xu A) versus t results
A semilog plot
-
linear portion of the curve will
the slope of the terminal
and if Ka > Ke, be estimated
The absorption rate constant Ka can
define Kg Of the drug. same data i.e. equation
9.82.
of residuals using the
by the method
administration can also be treated
excretion data after oral
Urinary construction of
slope- to Wagner-Nelson
calculate
method to K by
according collection for sufficiently long
% ARA plots. The method requires urine collected to
accurate estimation of Ke but need not be
time to ensure
with urinary
to relate % ARA
time infinity. The equation derived
y-intercept 1/KE excretion rate is:
|100=l1dX,/dt+KX, 100 (9.83)
Fig. 9.11 Regular plot of Xy versus t h ARA=1-ÄA KEX
during constant rate i.v. infusion
line with slope
t yields a straight
Relationships for rate of excretion when the drug is administereu ASemilog plot of % ARA versus
can also be given similarly. Thus: -K/2.303.
excretion data is
possiD
determination of K, from urinary with rapid
curate since for drugs
dXu =KeX (9.71) only for drugs with slow rate of absorption
short intervals
of time is
dt absorp cction of urine samples at very
difficul
difficult.
 BIOPHARMACEUTICS AND PHARMAc OMPARTMENT MODELLING
292 Ch9 COMPARTM
MULTICOMPARTMENT MODELs
(Delayed Distribution Models)
coKINETICS fulticompartment characteristics
drug of a
best understood are
293
i.v. bserving
bolus and obse the manner in which the
by
model adequately cribes npharmacokinetics
describes ha. at it
concentration
as
declines with tir plasma
One-compartment ponentials reai
giving
equilibriu.
Concehe such a plasma level-tine profile determines the number of
Instantaneous distribution is
many drugs.
cases and decline in the amount of drug in the body with assumed in such criD m0geneous compartmerts into which
drug will distribute.
1o deso
a
with a monoexponential term
expressed by an equation distribution is not (i.e.
truly possih le minat
time
However, instantaneous for an TWO-COMPARTMENT OPEN MODEL
and drug disposition is not
ntial even
larger number drugs
of monoex
bi- or multi-exponential.
This is because the oody is The cor
a c t of all
multicompartment models is a
two-compart
degreecomposed
el. In such a del, the body tissues are broadly classified
of tissues different
each with
heterogeneous group of
affinity for drug
and therefore ferent rates of equilibr
blood flow ment
i n t o 2 c a t e g o r i e s -
and
ally, a true pharmacokinetic model shou be the one withoration. Ide Centra Compartment or Compartment 1 comprising of blood
1.
tissue undergoing equilibr which is a rate and highly perfused tissues like liver, lungs, kidneys, etc. that
constant for each
models are thus based
difficul math- uilibrate with the drug rapidly. Elimination usually occurs
ematically. Multicompartment on
assumptions- lowing from this compartment.
1. Blood/plasma and the highly perfused tissues such as Peripheral or Tissue Compartment or Compartment 2 com-
poorly
of perfused and slow equilibrating
tissues such as
heart, lung,
liver and kidneys constitute the central
ompart
prising
muscles, skin, adipose, etc. and considered as a hybrid of several
ment.
functional physiological units.
2. Other tissues with similar distribution characieristics are pool,
together to constitute peripheral compartment tissues on the Classification of a particular tissue, for example brain, into central or
the physicochemical properties of
basis of similarity in their distribution characteristics. neripheral compartment depends upon
the drug. A highly lipophilic drug can cros the BBB and brain would
3. Intravenously administered medications are introduced directu the central compartment. In contrast, a polar drug
into the central compartment. then be included in
cannot penetrate the BBB and brain in this case will be a part of
4. Ireversible drug elimination, either by hepatic biotransformation the fact that it is a highly perfused
peripheral compartment despite
or renal
excretion, takes place only from the central compart- organ.
ment.
The plasma concentration for a drug that follows a two-compartment
5. Reversible distribution occurs between central and model declines biexponentially as the sum of two first-order processes
peripheral
compartments, with a finite time required for distribution equi- distribution and elimination.
librium to be attained.
Depending upon the compartment from which the drug is eliminated
6. After drug equilibration between central and the the two-compartment model can be categorized into 3 types:
peripheral com
partments, elimination of drug follows first-order kinetics. model with elimination from central compar
.Two-compartment
1. All rate processes involving passage of drug in and out o ment.
Indvidual compartment are first-order processes and plasma Two-compartment model with elimination from peripheral com-
level-time curve is best described by sum of series of expoucu partment.
al terms each corresponding to first-order rate proceses Wo-compartment model with elimination
from both the com-
associated with a given
compartment. partments.
8. The
peripheral compartment is usually inaccessible to u ect
is assumed to occur
measurement and is not a site of drug elimination
c e absence of information, elimination
cleara or
Cxclusivelyfrom central
compartmen
 penipheral
log drug concentration l
compartment
compartmecentral
 BIOPHARMACEUTICS AND PHARMACOKINE TMENT MODELLING
296 OMPART
291
Kz1 that depict revereil.,le the terminal linear
Ki2 and t
yield
phase of the curve
The constants
compartments
are alled as microconstants
ortransfer of
dn
plor
ofC
v e r s u s
303 and when back extrapolated
t
having
zero, yields y-
wbridtrans
beween The t
andnsfer miccoro.m
mathematical relationships between 9.13.). for the elimination phase
B (Fig.
stants The slo log tion ty = 0.693/B. can be
constants are given as
c d f r o m e q u a t i o n
interc
a+B=Ki2+K21 +KE obtaine
Subtraction o fe x t r a p o l a t a
plasma concentration values of the
hase (equation 9.9 m the elimi
9 90 corresponding true
afß = K21KE es (equation 9.92) yields series of residual plasma
n a t i o n p h a s e
concentratIon values (ed a
concen-
Equation 9.88 can be written in simplified form as 99 tration values C.
r
C, =C-C = Ae "
C Ae" +Be-*
(9.97)
becomes:
the equation
C Distribution exponent + Elimination exponent 992) In
log
form,
ot
also hybrid constants for the two logC, log A- 2.303
=
(9.98)
where A and B are
exponents
the method of residuals. and can
be resolved graphically by plot of C, versus t yields a straight line with slope
A semilog plot
A (Fig. 9.13).
y-intercept log
A-Xo K-a-CKz-a
V -a
303 and
-u2.3
B-a 9.93) log Co
logA
Va-B a-B 9.94) - log B
where Co =
plasma drug concentration immediately after i.v. iniectian back extrapolated terminal portion
Method of Residuals : The biexponential disposition curve obtained
of elimination phase (logCvalues)
after iv. bolus of a that fits
resolved into its individual
drug two compartment
the method of
model canbe true plasma concentration
Curve (log C values)
exponents by residuals. Re
writing the equation 9.92: residual line (log Cr values)
C = Ae+ Be- slope B/2.303
(9.92)
As apparent from the biexponential slope a/2.303
curve given in Fig. 9.12, the
initial decline due to distrib1 tion is more rapid than the terminal decline
due to elimination i.e. the rate constant a >> B and hence the term time
e
approaches zero much faster ihan does e . Thus, equation 9.92 reduces
Fig. 9.13 Resolution of biexponential plasma concentration
to time curve the method of residuals for a drug
by
that follows
administration.
two-compartment kinetics on i.v. bolus
C Bet (9.95)
V Bolus
In Pharmacokinetic Parameters
-
log form, the equation becomes: ASsessment of
Administration the method of
be resolved by
log C=log B (9.96) id
parameters of equation 9.92 can
of the model
viz. Ki2,
2.303 residuals as described above.Other parameters values.
where C substitution ofthese
=
back extrapolated plasma concentration values. A semilog
E e t c . can now be derived by proper
 298
BIOPHARMACEUTICS AND PHARMAC (MPARTMENT MODELLIN
301
Co A+B he phurmacokinetic
okinetic parameters also be calculated
by ush
r y CxCrclion data:
alC
K A+ Ba
dXu-K,
dt
V (9.109)
ation 9.92 can be derived for rate of
K.s = AB(-a) An cyupion

n identical
drug in
in urine:
2CoAN+Ba) etion of
unchanged
drug
t
Aß + Ba
exc
dXu =K, Ae"l +K, Be (9.110)
K21 dt
Co
9J02 uation
The above equa
can be resolve into individual exponents by the
It must be noted that for two-compartment model, K.
K is the siduals as
described for plasma concentration-time data.
elimination of drug from the central compartr
constant for ale nmelho given as:
the rate constant for elimination jrom the entire body. Ov and is Renal
clearance
is
tion tu, should theretore
be calculated from B. elimina ClR =Ke V (9.111)
Area under the plasma concentration-time curve can be ohtoi. Two-Compartment Open Model
the following equation: od by
Intravenous I n f u s i o n
as shown below with elimination from
AUC A4B The model can be depicted
aB 9.103) the central compartment.
The apparent volume of central compartment Ve is given as:
Ro Central Peripheral
Xo Compartment Ka Compartment
VaC
Co K AUC (9.104)
Apparent volume of peripheral compartment can be obtained from
equation: that fits
concentration of a drug
or central compartment (zero-order)
The plasma as constant
rate
12 model when
administered
(9.105) two-compartment
K21 i.v. infusion, is given by equation:
The apparent volume of distribution at equilibrium
steady-state or
can now be defined as: C Ro1+KE-B - ,
C a-p
(9.112)
VKE - a )
a.ss =Ve+V 9.106)
at time infinity), the
second and the
third term in
It is also
given as: At steady-state (i.e.zero and the equation reduces to:
the bracket becomes
Vd.area Xo
AUC (9.107) Ro (9.113)
Total systemic clearance is
BAUC
CsVKE
given as:
(9.108)
Cl =BVa
 300 BIOPHARMACEUTICS AND PHARMACOKINE Ch-9 COMPART
TMENT MODELLING
301
Va8. Substituting this in equation
tion order
btain all the
Now VK =
9.113, we
t i m e s

in
the method can be
necessary kinetic constants
get ifferent plexity, applied to drugs that
CVRo ClRoT
espite i
n a n y n u m

ber of compartments.
b e

distrib-
ute
The loading dose Xo.L to obtain ss immediatcly a
at
9AA true plasma concentration
curve (log C values)
be calculated
from equation: the log
N
infusion can
slart of back extrapolated distribution
XoL =CssV: Ro curve (log C -C) values)
KE log back extrapolated elimination
Two-Compartment Open Model
9.115 log M FF
curve (log C) values)
Extravascular Administration-First-Order ption first residual
be depicted as follows:
curve (log C values)
The model can
second residual (absorption)
line (log C, 2Values)
Central
Compartment K Peripheral slope B/2.303
Compartment
slope a/2.303
slope - K/2.303
time
For a drug that enters the body by a first-order
absorption
and distributed according to two-compartment model, the process
rate of chanoe Fig. 9.14 Semilog plot
of C versus t of a drug with two-compart
in drug concentration in the central when administered extravascularly. The various
compartment is described by ment characteristics
exponents-an absorption exponent, and the two usual exponents that3 exponents have been
resolved by the method of residuals.
describe drug disposition.
The plasma concentration at QUESTIONS
any time t is given by equation:
1. In one-compartment open model,
what do you infer from plasma being
C =Neal +Le"a+Me ßt (9.116)
called as reference compartment?
2. In compartment modelling, what does the term open mean?
C Absorption exponent + Distribution exponent + one-compartment kinetics is
a
Elimination exponent 3. Disposition of a drug that follows
where Ka, a and p have usual monoexponential process. Explain.
meanings. L, M and N are coefficients. 4. do first-order rate equations require logarithmic
transformations?
The 3 Why
exponents be resolved
can
by stepwise .With examples, explain what you understand by primary and secondary
of residuals assuming K > a> ß as shown application of method
in The various
pharmacokinetic parameters can then be estimated.Fig. 9.14. parameters.
only be used to estimate
the apparent
Besides the method of 1he expression Va =XC can
kinetics
that follows one-compartment
residuals, K, can also be estimated by Lo O I distribution of a drug
Riegelman method for a drug that When administered as i.v. bolus. Why?
follows two-comparu ent elimination rat
characteristics. This method is
in contrast to the
Wagner-Nelson m learance is a more important parameter than
half-life or
Explain,.
1Or determination of K, of a drug with dntin expressing elimination characteristics of a drug.
The Loo-Riegelman method requires one-compartment characics clearance.What are the
8. Define clearance,
data total body clearance and organ
DOn arter
oral and i.v. plasma concentration- an individual
organ
level?
administration of the drug to the same suoj a expressing clearance at
6