pharmacokinetics is the important topic in both pharmacology and pharmaceutics in degree and masters level . the thorough knowledge in the fiels of pharmacokinetics will helps to choose the proper medicine to treat a particular disesse

1. Non linear
pharmacokinetics :
causes of non-linearity
ALBIN T THOTTANKARA
SECOND SEM M.PHARM
DEPT. OF PHARMACEUTICS

2. INTRODUCTION
Linear models assume that pharmacokinetic parameters for a drug would not
change when different doses or multiple doses of a drug is given.
With some drugs increased doses or chronic medication can cause deviations from
the linear PK profiles . This is called as non-linear or dose-dependent
pharmacokinetics.
Drug ADME involve enzymes or carrier mediated systems. When these processes
are saturated at therapeutic levels , nonlinear PK behaviour is possible.
Besides saturation of plasma protein binding or carrier mediated systems, drug
may demonstrate non linear PK due to a pathologic alteration in drug ADE.
Eg . Aminoglycoside – renal nephrotoxicity – altering renal drug excretion
Gall stone obstruction of bile duct – alter biliary excretion

3. 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
Semi log plot for concentration v/s 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

4. Detection of non linearity
Determination of steady state plasma concentration at different doses
If: Css α Xo (Linear)
Determination of some important pharmacokinetic parameters
F, t1/2, Cl etc. are constant, any change show nonlinearity

5. Stages at which Nonlinearity occur
Nonlinearity 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

7. During Distribution
Saturation of binding sites on plasma proteins
eg. Phenylbutazone, naproxen.
Saturation of tissue binding sites
eg. Thiopental, fentanyl

8. During Metabolism
Capacity limited metabolism due to enzyme or cofactor saturation .
eg. Alcohol, Phenytoin.
Enzyme induction
eg. Carbamazepine

9. During Excretion
1. Renal excretion
2. Biliary excretion

10. Test for non linearity
1. Determine the steady state plasma concentration of the drug at different
doses.
If this concentration is directly proportional to the doses Kinetics is linear. If
it is not proportional kinetics is nonlinear.
•2. Determine some important pharmacokinetic parameter like fraction
bioavailable, elimination half life or total systemic clearance at different
doses of a drugs.
•If values are constant at different doses Kinetics is Linear and if the values
changes Kinetics is non-linear.

22. Lineweaver –Burke plot/ Klotz plot

24. Direct linear plot

25. The third graphical method