One-Compartment Open Model

Extravascular Administration
 When a drug is administered by extravascular route ,the rate of absorption may
be described by mathematically as a zero or first order process.
 A large number of plasma concentration time profile can be described by a one
compartment model with first order absorption & elimination.
 Difference between zero- order and first- order kinetics are given in fig.
 One-Compartment Open Model
Extravascular Administration
 Zero order absorption is characterized by a constant rate
of absorption .
 After e.v. administration , the rate in the change of amount
of drug
the bodyindx/dt is difference between the rate of input (absorption)
dxev/dt and rate of output( elimination) dxE/dt .
 dx /dt = rate of absorption – rate of elimination

dx dx e v dx E …(1)
dt  dt - dt
 One-Compartment Open Model
Extravascular Administration
 During the absorption phase, the rate absorption is greater than
the rate of elimination
dxev dx E …(2)
dt  dt
 At peak plasma concentration , the rate of absorption equals the
rate of elimination and the change in amount of drug in the body
is zero
dx dx …(3)
ev  E
dt  dt
 The plasma level time curve is characterized only
byElimination
the phase. …(4)
dx e v dx E

 Zero- Order
Absorption Model
Extravascular

Administration
 Zero - Order Absorption Model
Extravascular Administration
 This model is similar to that for constant rate infusion.

R0 Blood and
Drug at KE Elimination
other
Zero order body
e.v.site tissues
absorption

 All equation that explain the plasma concentration – time

profile for constant rate i.v. infusion are also applicable
to this model.
 First order
Absorption Model
Extravascular
Administration
 First order Absorption Model
Extravascular Administration
 A drug that enters the body by a first order absorption process gets
distributed in the body according to one - compartment kinetics and
is eliminated by a first - order process, the model can be depicted
as follows
Blood and
Drug at Ka KE Elimination
other
First order body
e.v.site tissues
absorption
 The differential form of the drug the eque.
(1)
dx …(5)
dt  k x - k x
a a E

 Ka = first order absorption rate constant

 Xa = amount of drug at the absorption site remaining to
be absorbed i.e. ARA.
 First order Absorption Model
Extravascular Administration
 Integration of eque. (5)

X 
K a FX 0
[e
KEt e
K
at
] …(6)
(K a – K E )
Transforming in to concentration terms, the eque. Becomes
Ka FX 0 k
C e at
] …(7)
k
Where, [e Et

Vd(K asystemically
F= fraction of drug absorbed - KE ) after e.v.
administration .
Assessment of
Pharmacokinetic
Parameters
Extravascular
administration
Assessment of Pharmacokinetic Parameters
Extravascular administration
 Cmax and tmax : At peak plasma concentration , the rate of absorption
equals rate of elimination i.e. KaXa =KEX and the rate of change in
plasma drug concentration dc/dt = zero . Differntiating equation(7)

dc K a FX 0[K E k t
 Ka k t
] …(8)
 e E e a

Zero
dt Vd(K a - K E )
 On simplifying ,the above eque. Becomes:
…(9)
K ek t
 K -k
e at
E E a

 Converting to logarithmic
form, k Et k at
log kE  log ka …(10)
- 2.303 - 2.303
Assessment of Pharmacokinetic Parameters
Extravascular administration
 Where t is tmax . Rearrangement of above eque. yield:

Tm a x  2.303log ( K a /K E ) …(11)
Ka - E
K
 Cmax can be obtained by substituting eque. (11) in eque (7), simpler eque
for the same is:

C m a x  FX 0 e  k E tm a x
…(12)
Vd
 It has been shown that at Cmax, when Ka = KE, tmax = 1/KE.
Hence the above eque. Further reduced to:

C m ax  FX 0 e1  0.37 FX 0 …(13)

Vd Vd
Since, FX0/Vd represent C0 .
https://www.youtube.com/watch?v=9W_kwn7ZHtI
Elimination Rate Constant
 Elimination Rate Constant
 The parameter can be computed from the elimination phase of the p
level time profile.
 For most drugs administered e.v., absorption rate is significantly grea
than the elimination rate.
 At such a stage, when absorption is complete, the change in plasma
conc. Is depend only on elimination rate and eque. (7) reduces to

C  K a FX 0 k
…(14)
V d (K a - K E ) e Et

 Transforming into log form, the eque. Becomes ,

Ka FX0  KE t
…(15)
log C 
log Vd(Ka - KE )
2.303
Absorption Rate Constant
 Absorption Rate Constant
 It can be calculated by the method of residuals.
 For a drug that follow one compartment kinetics & administered e.v., the
concentration of drug in plasma is expressed by a biexposnential equation
(7)
Ka FX -K
C  0
[e  KE t e a t
]
Vd (K a - …(14)
KE )
if K a FX 0 /Vd (K a - K E )  A, a hybrid constant then
: -k t -k t …(15)
 C  Ae Ea -
 During the elimination phase,
Ae when absorption is almost over, Ka>KE value
of second exponential e-Kat is zero. Whereas the exponential e-KEt retaines some finite
value. at this time the eque.(15) reduced
to:

-K E t
C  Ae …(16)
 In log form, the above equation is:

 K Et
log C  log A …(17)
- 2.303
 Absorption Rate Constant
 Where, C represents the back extrapolation plasma
concentration value.

 Substraction of true plasma conc. Values i.e. equa.(15) from

the extrapolated plasma concentration values Cr

-Ka
(C C)  rC  t
…(18)
Ae
 Absorption Rate Constant

 In log form, the

eque.is
Ka t
log Cr  logA …(19)
- 2.303

 A plot of log Cr vs t yields a straight line with –Ka/2.303 &

y intercept log A
 In some instance , the KE obtained after i.v. bolus of some
of the drug is very larger than the Ka obtained by recidual
method and KE/Ka> 3,