This document discusses linear and non-linear pharmacokinetics. Linear pharmacokinetics follow first-order kinetics where the rate of drug elimination is directly proportional to drug concentration. With non-linear kinetics, the rate of elimination appears zero-order at higher concentrations as a constant amount is eliminated per unit time. Non-linear kinetics occur when absorption, distribution, metabolism or excretion processes become saturated at higher doses. This can be detected by determining how pharmacokinetic parameters change with different doses. Causes of non-linearity include saturation of transporters, binding proteins, metabolic enzymes and renal reabsorption/secretion mechanisms.

1. Non Linear & Linear
P’Kinetics
DEEPAK RAJPUT
M.PHARMA PHARMACOLOGY 1ST SEMESTER
I.T.S COLLEGE OF PHARMACY

2.  All the rate process follows first order kinetics even elimination process also consumed to follow
first order kinetics i.e. "First-order kinetics... is where a constant fraction of drug in the body is
eliminated per unit of time“ . All enzymes and clearance mechanisms are working at well below
their maximum capacity, and the rate of drug elimination is directly proportional to drug
concentration
 But at higher concentration elimination appears as zero order i.e. a constant amount (eg. so many
milligrams) of drug is eliminated per unit time.
 First order kinetics is a concentration-dependent process (i.e. the higher the concentration, the
faster the clearance), whereas zero order elimination rate is independent of concentration.
 And at lower concentration it becomes first order.
 Generally at therapeutic dose the change in plasma concentration due to A,D,M,E is proportional
to its dose. Whether administered single or as multiple dose.
Cp α Dose= Dose/ volume

3.  This is called first order or linear kinetics and a graph plotted b/w concentration and time
and the important pharmacokinetic parameter like F, Ka, KE, Vd, CLR & ClH which shows
time course of drug in the body are not affected by the dose i.e. dose independent.
But in some cases ADME depends on carrier on enzymes that are substrate specific have
definite capacities and susceptible to saturation at high drug concentration. In such cases first
order kinetics changes in to mix of first order and zero order rate process and the
pharmacokinetic parameter changes with the size of administered dose. The pharmacokinetic
of such drug are called as dose dependent or mixed order or non linear or capacity limited
kinetics.

4.  Linear means rate of elimination is proportional to amount of drug present. Dosage increase
result in proportional increase in plasma drug level.
 Non linear means rate of elimination is constant regardless of amount of drug present.
Dosage increase saturate binding sites and result in non proportional increase/decrease in
drug level.

5. Difference b/w Linear and Non linear
Linear Non linear
The pharmacokinetic parameter of these drug is
not expected to change when different doses are
administered or when drug is given through
different route of administration or as single or
multiple dose.
The kinetics of such drug is dose independent,
first order kinetics.
Rate α concentration of drug
The average steady state concentration may
increase. With some drugs, increased dose or
chronic medication can cause deviation from the
linear pharmacokinetic is known as Non linear
kinetics.
For these drugs the kinetic parameter like
clearance, Vd, t1/2 may vary depending on the
administered dose. This is because one or more
of the kinetic process of the drug ADME may be
via a process other than simple first order
kinetics.
Rate of elimination α 1/Cp

6. Test to detect Non linearity
1. Determination of steady state plasma concentration at different doses: if steady state α dose
then linearity in the kinetics exist. If this proportionality is not, then there is no linearity.
2. Determination of important pharmacokinetic parameter: fractional bio-available, Elimination Half
life, Total Systemic clearance at different doses of drug. Any change in these parameter is
indication of non linearity.

7. Causes/ source of Non linearity
1. Drug absorption: Non linearity in drug absorption arises from 3-imp sources:
a) When absorption is solubility or dissolution rate limited: Exp. Griseofulvin. At higher dose, a saturated
solution of the drug is formed in the GIT and rate of absorption attains a constant value.
b) When absorption involves carrier mediated transport system: Exp. Absorption of riboflavin, ascorbic
acid, cyanocobolamine. Saturation of transport system at higher doses of these vitamin result in Non
linearity.
c) When presystemic gut wall or hepatic metabolism attains saturation. E.g. Propanolol

8. 2. Drug distribution: Non linearity in distribution of drug at high dose may be due to-
a) Saturation of binding sites or plasma protein: Exp Phenylbutazone and Naproxen.
At high dose too much fraction remain unbound.
b) Saturation of tissue binding site: Exp Thiopental & Fentanyl. With large single bolus dose or multiple
dosing, saturation of tissue storage site can occur.
In both cases free plasma drug concentration increases but Vd increases only in former case and decrease in
later case.

9. 3. Drug metabolism: two important causes of Non linearity in metabolism are-
a) Capacity limited metabolism due to enzyme/cofactor saturation: Exp Phenytoin, alcohol,
Theophylline etc.
b) Enzyme induction: Exp carbamazepine. A decrease in peak plasma concentration is observed on
repetitive administration over a period of time.
saturation of enzyme decreases ClH and increases Css. Non linearity may be due to saturation of binding
site, pathological conditions like hepatotoxicity, change in hepatic blood flow.

10. 4. Drug Excretion: Two active process in renal excretion that are saturable are-
a) Active Tuular Secretion: Exp Penicillin G. after saturation of carrier system, a decrease in renal
clearance occur.
b) Active tubular reabsorption: Exp water soluble vitamin & glucose. After saturation of carrier system
an increase in renal clearance occur.
other causes of Non linearity is force of diuresis, change in urine pH, nephrotoxicity, saturation of
binding site.

11. Thank You