Dr. M.

Mothilal
Assistant professor
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.
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.

` 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.
 Non linearity can occur at any of the following stage during
the fate of drug in body:

` Absorption
` Distribution
` Biotransformation/Metabolism
` Excretion
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
During Distribution

` Saturation of binding sites on plasma proteins eg.

Phenylbutazone, naproxen.

` Saturation of tissue binding sites eg. Thiopental, fentanyl.

During Metabolism

` Capacity limited metabolism due to enzyme or cofactor

saturation eg. Alcohol, Phenytoin.

` Enzyme induction eg. Carbamazepine

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.
` 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
` 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

dC/dt
2 at high doses

Mixed order rate

at intermediate
doses

First order rate at

low doses
Km
Concentration
` 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
 Log Co

Log Co

Log C

Terminal linear portion

with slope= –Vmax/2.303
Km

Time (t)
` 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.
` 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
` Lineweaver Burke Plot
1 = Km + 1
DR Vmax.Css Vmax

1/DR
Slope = Km/Vmax

1/Vmax

1/Css
` Direct Linear plot

DR Vmax

DR1

DR2
Slope = Km/Vmax

Css1 Css2 Km

Css Km
` Graphical Method

DR = Vmax _ Km DR
Css
` Plot between DR and DR/Css yield straight line with
slope: –Km, &
y- intercept: Vmax
¾ Biopharmaceutics and pharmacokinetics.
P L Madan, no 1st edn.
¾ Biopharmaceutics and pharmacokinetics.
D.M Brahmankar and Sunil. B .Jaiswal,1st edn
¾ Applied Biopharmaceutics and pharmacokinetics
Leon shargel and Andrew Yu,4th edn.
¾ Biopharmaceutics and clinical pharmacokinetics By Milo
Gibaldi, 4th edn.