UNIT 4
Non Linear Pharmacokinetics
S. SANGEETHA., M.PHARM., (Ph.d)
Department of Pharmaceutics
SRM College of Pharmacy
SRM University
Difference between Linear and
non linear pharmacokinetics
Linear pharmacokinetics
• Change in plasma concentration due to ADME
process is proportional to dose of drug
administered (single or multiple)
• Follow First order kinetics
• Semilog plot for concentration vs time is super
imposable (Principle of superimposition)
• No change in F, Ka, Ke, Vd, Clearance etc.
Difference…………...contd.
Nonlinear Pharmacokinetics
• Rate process of ADME are dependent on carrier
or enzymes having definite capacity and
subjected to saturation.
• Change in concentration is no more proportional
to dose administered during the total process of
ADME.
• Follow First order + Zero order kinetics
• Change in different pharmacokinetic parameters.
Detection of non linearity
• Determination of steady state plasma
concentration at different doses
If: Css α Xo (Linear)
Css α Xo (Non linear)
• Determination of some important
pharmacokinetic parameters
F, t1/2 , Cl etc. are constant, any
change show nonlinearity.
Stages at which Nonlinearity occur
Non linearity can occur at any of the following
stage during the fate of drug in body:
• Absorption
• Distribution
• Biotransformation/Metabolism
• Excretion
Causes of Nonlinearity
During absorption
• Absorption is solubility or dissolution rate limited
eg. Griseofulvine
• Absorption involve carrier mediated
transportation eg. Riboflavin, ascorbic acid
• Hepatic metabolism attain saturation eg.
Propranolol, hydralazine
Causes………………….contd.
During Distribution
• Saturation of binding sites on plasma proteins
eg. Phenylbutazone, naproxen.
• Saturation of tissue binding sites eg.
Thiopental, fentanyl.
Causes………………….contd.
During Metabolism
• Capacity limited metabolism due to enzyme or
cofactor saturation eg. Alcohol, Phenytoin.
• Enzyme induction eg. Carbamazepine
Causes………………….contd.
During Excretion
• Active tubular secretion eg. Penicillin G
• Active tubular re‐absorption eg. Glucose, water
soluble vitamins.
• Other sources: Forced Diuresis, change in urine
pH, nephrotoxicity etc.
Michaelis Menten Equation
• Nonlinear pharmacokinetics can be best
described by Michaelis Menten Equation.
_ dC Vmax . C
dt Km + C
Where:
dC/dt : rate of decline in drug conc. with time
Vmax : theoretical maximum rate of process
Km : Michaelis constant
Equation………………contd.
• When Km = C
_ dC Vmax
dt 2
• When Km>>C
_ dC Vmax.C
dt Km
• When Km<<C
_ dC Vmax
dt
Vmax
Vmax Zero order rate at
dC/dt
2 high doses
Mixed order rate at
intermediate doses
First order rate at low
doses
Km
Concentration
Estimation of Km and Vmax
• Integration of Michaelis Menten Equation
log C = log Co + (Co – C) – Vmax
2.303Km 2.303Km
• Semilog plot of C vs t yields a curve with terminal linear
portion, which on back extrapolation to time zero give
y intercept log Co.
log C = log Co – Vmax
2.303Km
Km and Vmax....……....contd.
Log Co
Log Co
Log C
Terminal linear portion with
slope= –Vmax/2.303 Km
Time (t)
Km and Vmax....……....contd.
• At low plasma concentration:
(Co – C)/2.303 Km = log Co/Co
So Km can be obtained from this equation
while Vmax can be obtained from slope by
putting value of Km.
Estimation of Km and Vmax
(steady state)
• In case of I.V. infusion a steady state
concentration is maintained by a suitable
dosing rate (DR).
• This DR at steady state equals rate of
elimination.
• So Michaelis Menten equation can be written:
DR = Vmax . Css
Km + Css
Km and Vmax (Steady state)....contd
• Lineweaver Burke Plot
1 = Km + 1 .
DR Vmax.Css Vmax
1/DR
Slope = Km/Vmax
1/Vmax
1/Css
Km and Vmax (Steady state)....contd
• Direct Linear plot
DR Vmax
DR1
DR2
Slope = Km/Vmax
Css1 Css2 Km
Css Km
Km and Vmax (Steady state)....contd
• Graphical Method
DR = Vmax __ Km . DR
Css
• Plot between DR and DR/Css yield straight line
with
slope: –Km, &
y‐ intercept: Vmax
