Professional Documents
Culture Documents
CONTENTS
Introduction
Causes of nonlinearity
#
»The important pharmacokinetic parameters viz.
F, Ka, KE, Vd, ClR, ClH
which describes the time course of a drug in the body remain
unaffected by the dose.
» Pharmacokinetics is dose independent.
#
NONLINEAR PHARMACOKINETICS
#
Examples of drugs showing nonlinear pharmacokinetics
Causes Drugs
GI absorption:-
Saturable transport in gut wall Riboflavin, Gabapentin
Saturable GI decomposition Penicillin G, Omeprazole
Intestinal metabolism Propranolol, Salicylamide
Distribution:-
Saturable plasma protein binding Phenylbutazone, Lidocaine
Tissue binding Imipramine
Metabolism:-
Saturable metabolism Enzyme Phenytion, Salicylic acid
induction Metabolite inhibition Carbamazepine
Renal elimination:- Active Diazepam
secretion Tubular reabsorption
Change in urine pH Para- aminohippuric acid
Ascorbic acid, Riboflavin
Salicylic acid, Dextroamphetamine
#
• Example of Phenytoin
https://www.youtube.com/watch?v=RO4nALnWQtk
youtube.com/watch?v=UvnBmvVyD0M
https://www.youtube.com/watch?v=90noN
X9XMy0
For numerical
https://www.youtube.com/watch?v=DfjyFfr-
mus
MICHAELIS MENTEN ENZYME
KINETICS
E+D ED E +M
#
MICHAELIS MENTEN EQUATION
• The kinetics of capacity limited or saturable processes is best described
by Michaelis-Menten equation.
dC Vmax . C
= ……………….. I
dt KM+ C
Where ,
-dC/dt = rate of decline of drug conc. with time
Vmax = theoretical maximum rate of the
process
KM = Michaelis constant
• above eq. is identical to the one that describe first order elimination of
drug, where Vmax/KM= KE.
3) When KM<<C:
•Under this condition ,K M +C= C and eq. I will become,
-dC/dt =Vmax …………….IV
above eq. is identical to the one that describe a zero order process i.e.
the rate process occurs at constant rate Vmax and is independent of
drug conc.
E.g. metabolism of ethanol #
Zero order rate at high doses
Mixed order rate at
intermediated doses
Dc First order rate at low doses
dt
C
Figure 1
A plot of
MME
#
ESTIMATION OF Vmax & Km
#
Method 1
By reciprocating equation (1), we get :
1 = Km . 1 + 1 ……..(2)
V Vmax . C Vmax
#
Km/Vmax
1/ Vmax
-1/ Km
Figure 2
Plot of 1/V vs 1/C for determining Km & Vmax
Multiplying eq. 2 by C, we
get :
#
ax
ax
Figure 3.
Plot of C/V vs C for determining Km & Vmax
#
Method 3
V = - Km V + Vmax
…………(4)
C
#
Figure 4
Plot of V vs V / C for determining Km & Vmax
#
CALCULATION OF KM & VMAX
STEADY- STATE CONCENTRATION
• If drug is administered for constant rate IV infusion/ in a
multiple dosage regimen, the steady-state conc. is given in terms
of dosing rate (DR):
DR = Css ……………….. (1)
ClT
• If the steady-state is reached, then the dosing rate = the rate of
decline in plasma drug conc. & if the decline occurs due to a
single capacity-limited process then eq. I become as:
Vmax Css
DR = ……………….. (2)
KM+ C ss
Css
Km
Vmax / 2 Vmax
DR (in mg/hr or mg/day )
Figure 5
#
METHODS USED TO
DETERMINE THE
KM & VMAX AT
STEADY-STATE
#
• There are three methods which are used to define the K M & Vmax
at steady-state with appreciable accuracy:
1) Lineweaver-Burk Plot:- the reciprocal of eq. (2) we get
1 KM 1
= ……………….. (3)
DR Vmax Css +
Vmax
DR
Vmax
DR1
DR2
KM
Css 1 Css 2
0 KM
Css
#
Figure 6
3) Graphical
method:-
DR
DR/Css
Figure 7
Plot of DR vs DR/Css for determining Km &
Vmax #
3) Graphical
• method:-
In this method by rearranging eq. (2) we get
KM DR ……………….. (4)
DR = Vmax
Css
-
Css1
……………….. (6)
DR2 = Vmax -
KM DR2
Css2
#
• On solving above eq. 5 & 6 we get,
DR2- DR1
KM = DR1 DR2 ……………….. (7)
-
Css 1 Css 2
• By substituting values of DR1, DR2, Css1 & Css2 we get value of KM &
from KM we can found value of Vmax at steady-state
concentration.
•
From experimental observations, it shows that KM is much less
variable than Vmax.
#
REFERENCE