ONE COMPARTMENT OPEN

MODEL
IV BOLUS administration
 Assumption
The body is considered as a single, kinetically homogeneous unit that has no barriers to the
movement of drug.

Final distribution equilibrium between the drug in plasma and other body fluids (i.e. mixing) is
attained instantaneously and maintained at all times. This model thus applies only to those drugs
that distribute rapidly throughout the body
Drugs move dynamically, in (absorption) and out (elimination) of this compartment

Elimination is a first-order (monoexponential) process with first-order rate constant

Rate of input (absorption) > rate of output (elimination)

The anatomical reference compartment is plasma and concentration of drug in plasma is

representative of drug concentration in all body tissues i.e. any change in plasma drug
concentration reflects a proportional change in drug concentration throughout the body
 Simply said…
• When a drug that distributes rapidly in the
body is given in the form of iv bolus injection,
it takes about 1 – 3 mins for complete
circulation.

• Thus rate of absorption is neglected

 Depiction of model

K10
1
• General expression for rate of drug
presentation to the body is:
dX
 Rate in (availabil ity) - Rate out (eliminati on)
dt

• Since, rate in or absorption is absent, the

equation becomes
dX
  Rate out
dt

• If rate out or elimination follows first order

kinetic
dX
 K E X
dt
(eq.1)
 Elimination phase
 Elimination phase gives three parameters:

• Elimination rate constant

• Elimination half life

• Clearance
 Elimination rate constant
• Integration of equation (1)
• X=Xo e-K t (eq.2)
e

• ln X = ln Xo – KE t ( eq.3)

Xo = amt of drug injected at time t = zero i.e.

initial amount of drug injected i.e. DOSE
K Et
log X  log X o 
2.303 (eq. 4)
• Since it is difficult to directly determine amount of drug
in body X, we use relationship that exists between drug
conc. in plasma C and X; thus

• X = VdC (eq. 5)
Where Vd – proportionality constant known as
apparent volume of distribution

• So equation-4 becomes
log C  log C 
(eq.6)
0
KEt
2.303
 Elimination rate constant
• It is an additive property.

• It is a sum of rate constants of all the elimination or

drug removal processes like urinary excretion,
metabolism, biliary excretion, pulmonary excretion etc

• KE = Ke + Km +Kb +Kl +….. (eq.7)

• KE is overall elimination rate constant

 Fraction of drug eliminated
• It can be evaluated if the number of rate constants
involved and their values are known

• Eg. If a drug is eliminated only by urinary excretion

and metabolism then, Km
Ke
Fe  Fm 
KE KE

• Where, Fe – fraction of drug excreted unchanged

in urine
Fm – fraction of drug metabolised
 Elimination half life
• Also known as biological half life

• Defined as the time taken for the amount of

drug in the body as well as plasma
concentration to decline by one-half or 50% its
initial value

• It is expressed in hr or min
 0.693
t1/ 2  (eq.8)
KE

Elimination half life can be readily obtained

from the graph of log C versus t
Half life is a secondary parameter that depends
upon the primary parameters such as clearance
and volume of distribution.
0.693Vd (eq.9)
t1/ 2 
ClT
 Apparent volume of distribution
• Defined as volume of fluid in which drug
appears to be distributed.
Amount of drug in the body X
Vd  
(eq.10)
Plasma drug concentrat ion C

Best way of estimating Vd is by giving an iv bolus

dose and determining the initial plasma
concentration

Vd 
X0

(eq.11)
iv bolus dose
C0 initial plasma conc
• Non-compartmental method that can be
applied to a variety of drugs is more useful to
study Vd
• For drugs given as iv bolus
X0
Vd ( area )  (eq. 12.a)
K . AUC
E

• For drugs administered ev

V 
FX 0 (eq. 12.b)
d ( area )
K E . AUC

Where, F = fraction bioavailable

 Clearance
• It is a parameter to characterize drug
disposition

• It is the most important parameter in clinical

drug applications

• It is useful in evaluating the mechanism by

which a drug is eliminated by the whole
organism or by a particular organ
• It is a parameter which relates plasma drug
concentration and rate of elimination as
follows
Rate of eliminatio n dX / dt
Clearance (Cl )  (eq. 
13)
Plasma drug conc C

• It is defined as the theoretical volume of body

fluid containing drug (i.e. that fraction of
volume of distribution) from which the drug is
completely removed in a given period of time

• Units – mL/min or l/hr

 Total body clearance
• Elimination of the drug from body involves various
organs
• Clearance at individual organ level is known as organ
clearance
• It can be estimated by dividing the rate of elimination
by each organ with the conc of drug presented to it
Re nal Clearance,
Rate of eliminatio n by kidney
Cl R 
C
Hepatic Clearance,
Rate of eliminatio n by liver
Cl H 
C
Other organ Clearance,
Rate of eliminatio n by other organs
ClOthers 
C
• Total body clearance (total systemic clearance)
is an additive property
ClT  ClR  ClH  ClOthers
• Clearance by all organs other than kidney is
called as non-renal clearance and is denoted
as ClNR

ClNR  ClT  ClR

 dX / dt
ClT 
C
dX
but ,  KE X
dt
KE X
ClT 
C
X
but ,  Vd
C
Thus,
ClT  K EVd
• Similar equation can be written for renal and
hepatic clearance
ClR  K eVd ClH  K mVd

0.693
Since, K E 
t1/ 2
• Clearance can be related to half life

0.693Vd
ClT 
t1/ 2
• Thus we can conclude that, as clearance
decreases (renal insufficiency) half life of the
drug increases

• As clearance depends on Vd, changes in Vd

(obesity, edema etc) change the clearance of
the drug
Non-compartmental method for clearance

• For drugs given as iv bolus dose

X0
ClT 
AUC

• For drugs given ev

FX 0
ClT 
AUC
• For a drug given by iv bolus route, renal
clearance maybe estimated by determining
the total amount of drug excreted unchanged
in urine and AUC

X
ClR  u
AUC
 Organ clearance
• It predicts and evaluates the effect of
pathology, blood flow, P-D binding, enzyme
activity etc on drug elimination
• At organ level, rate of elimination can be
written as:
Rate of eliminatio n by an organ  Rate of presentati on to the organ - Rate of exit from the organ

Rate of presentati on  Organ blood flow X Entering concentrat ion

 QCin
Rate of exit  Organ blood flow X Exiting concentrat ion
 QCout
• Rate of elimination is also called as Rate of
Extraction
Rate of eliminatio n  QCin - QCout
 Q (C in - C out )
• Dividing above eq by Cin, we get:

Rate of extraction Q(Cin  Cout )

 Clorgan   Q.ER
Cin Cin

where, ER = extraction ratio

 Extraction ratio
• ER is an index of how efficiently the
eliminating organ clear the blood flowing
through it of drug
• It has no units
• It ranges from zero (no elimination) to one
(complete elimination)
• Based on ER drugs can be classified into
Sr. no. Type of ER Value
1 High > 0.7
2 Intermediate 0.3 – 0.7
3 Low < 0.3
• Eg. An ER of 0.6 means that 60% of the blood
flowing through the organ will be totally
cleared off the drug
• The fraction of drug that escapes removal by
the organ is expressed as:
F = 1 – ER
F = systemic bioavailability when the eliminating
organ is liver
 Hepatic clearance
• For majority of drugs, the non-renal clearance
can be assumed as equal to hepatic clearance
ClH  ClT  ClR
ClH  QH .ERH
• Hepatic clearance of drugs can be divided into
2 groups
– Drugs with hepatic blood flow rate-limited
clearance
– Drugs with intrinsic capacity-limited clearance
Hepatic blood flow rate-limited clearance

• When ERH = 1, ClH approaches its maximum value

i.e. hepatic blood flow
• Here, hepatic clearance is said to be perfusion rate-
limited or flow-dependent
• Alteration in hepatic blood flow affects the
elimination of drugs having high ER significantly
• Eg. Propranolol, lidocaine
• Drugs with low ER are nor affected by changes in
blood flow
• Eg. theophylline
Intrinsic capacity-limited clearance (Clint)

• It is defined as the inherent ability of an organ

to irreversibly remove a drug in the absence of
any flow limitation
• In case of liver, it depends upon enzyme
activity
• Drugs with low ER and those which are
eliminated primarily by metabolism are
greatly affected by changes in enzyme activity
• Clearance of such drugs is said to be capacity-
limited

• It is independent on blood flow but sensitive

to changes in protein binding
 Extraction ratio
High Intermediate Low
Hepatic Propranolol Aspirin Diazepam
extraction Lidocaine Codeine Phenobarbital
Nitroglycerine Nortryptiline Phenytoin
Morphine Quinidine Procainamide
Isoprenaline Theophylline

Renal Some penicillins Some Digoxin

extraction Hippuric acid penicillins Furosemide
Several sulphates Procainamide Atenolol
Several Cimetidine Tetracycline
glucuronoids
Fraction of drug remaining in body
X  X oe KEt
X
  eK Et
X0
0.693
K E 
t1/ 2
0.693
X  t
 e t1 / 2

X0
n
X 1 t
    where n 
X0  2  t 1/2
n
1
 Fraction of dose remaining in body   
2
 Problems
1) An iv bolus dose (25 mg) of a drug following
one compartment kinetics has a Vd of 27000L
and a half life of 36 h. Calculate:
a) Concentration after 18 h of drug administration
b) Elimination rate constant and clearance
c) AUC (zero to infinity) of the drug
d) Amount remaining in the body after 42 h
e) % dose remaining after 30 h
f) Time required to eliminate 25% of the dose
[2011-12 (DK-9810)]
2) An iv bolus dose (5 mg) of a drug following
one compartment kinetics has a Vd of 270L
and a half life of 6 h. Calculate:
a) Concentration after 9 h of drug administration
b) Elimination rate constant, volume of distribution
and clearance
c) AUC (zero to infinity) of the drug
d) Amount eliminated from the body after 3 h
e) % dose remaining after 15 h
f) Time required to eliminate 75% of the dose
[2010-11 (DK-5547)]