Non - Linear Pharmacokinetics

CENTURION UNIVERSITY OF TECHNOLOGY AND
MANAGEMENT
BIOPHARMACEUTICS & PHARMACOKINETICS
NONLINEAR
PHARMACOKINETICS
UNDER THE GUIDANCE OF:- PRESENTED BY:-
HIMANSU BHUSAN SAMAL NAME : RINKU KUNDU(61)
ASSOCIATE PROFESSOR
BRANCH : B.PHARM (6TH SEM)
DEPARTMENT OF PHARMACEUTICS
INTRODUCTION
LINEAR PHARMACOKINETICS
In most cases, at therapeutic doses, the change in the amount of drug
in the body or the change in its plasma concentration due to
absorption, distribution, binding, metabolism or excretion, is
proportional to its dose, whether administered as a single dose or as
multiple doses.
In such situations, the rate processes are said to follow first-order or
linear kinetics and all semi-log plots of C versus t for different doses,
when corrected for dose administered, are superimposable. This is
called as principle of superposition.
The important pharmacokinetic parameters viz. F, Ka, KE, Vd, and
ClR which describe the time-course of a drug in the body remain
unaffected by the dose i.e. the pharmacokinetics is dose-independent.
NON-LINEAR PHARMACOKINETIC
The rate process of a drug’s ADME are dependent upon

carrier or enzymes that are substrate-specific, have definite
capacities, and susceptible to saturation at high drug
concentration.
In such cases, an essentially first-order kinetics transform
into a mixture of first-order and zero-order rate processes
and the pharmacokinetic parameters change with the size of
the administered dose. The pharmacokinetics of such drugs
are said to be dose-dependent.
Other terms synonymous with it are mixed-order, nonlinear
and capacity-limited kinetics.
DIFFERENCE BETWEEN LINEAR AND
NON-LINEAR PHARMACOKINETICS
LINEAR PHARMACOKINETIC NON-LINEAR

PHARMACOKINETIC
 Pharmacokinetic parameter for a  Pharmacokinetic parameter for a

drug would not change with drug can change with change in
change in dose dose
 Dose independent  Dose dependent
 Follow First order kinetics  Follow both Zero and First order
kinetics
DETECTION OF NON-LINEARITY
IN PHARMACOKINETICS
There are several tests to detect nonlinearity in
pharmacokinetics but the simplest ones are –
1. Determination of steady-state plasma concentration at
different doses. If the steady-state concentrations are directly
proportional to the dose, then linearity in the kinetics exists.
Such proportionality is not observable when there is
nonlinearity.
2. Determination of some of the important pharmacokinetic
parameters such as fraction bioavailable, elimination half-life
or total systemic clearance at different doses of the drug. Any
change in these parameters which are usually constant, is
indicative of nonlinearity.
FACTOR CAUSING NON-
LINEARITY
1. DRUG ABSORPTION
Generally, Non-linearity within drug absorption arise from 3
important factors,
When absorption is solubility / dissolution of drug is rate-
limited- at high concentration in intestine saturated solution
of drug is formed. Moreover, at any other extravascular site
and the rate of absorption achieve a constant value. For
instance, Griseofulvis
When absorption includes Carrier mediated transport
system- the saturation of transport system at higher doses of
such vitamins shows non-linearity. For example, Riboflavin
absorption.
When presystemic gut wall or hepatic metabolism attains
saturation - saturation of presystemic metabolism of drugs
like Propranolol, verapamil leads to increased
bioavailability.
These parameters affected will be F, Ka, Cmax and AUC.
A decrease in these parameters is observed in the former
two cases and an increase in the latter case.
Other causes of nonlinearity in drug absorption are
changes in gastric emptying and GI blood flow and other
physiologic factors.
2. DRUG DISTRIBUTATION
In drug distribution, at high doses non-linearity occurs due to the
two prime factors:
Saturation of binding sites occurring on plasma proteins. For
example, Phenylbutazone and naproxen. Due to limited number
of binding sites of specific drug on plasma protein saturation
occurs.
Tissue binding sites get saturated due to large single bolus doses
or multiple dosing.
In both cases, the free plasma drug concentration increases.
But Vd increases only in the case-1 whereas it decreases in the
latter.
Clearance of a drug with high Excretion Ratio(ER) is greatly
increased due to saturation of binding sites.
3. DRUG METABOLISM
Non-linearity occurs due capacity-limited metabolism since
small changes in dose administered can produce large
variations in plasma concentration at steady-state. Two
important causes of nonlinearity in metabolism are –
Capacity-limited metabolism due to enzyme and/or cofactor
saturation. Examples include phenytoin, alcohol, theophylline,
etc.
Enzyme induction e.g. carbamazepine, where a decrease in
peak plasma concentration has been observed on repetitive
administration over a period of time.
Autoinduction characterized in this case is also dose-
dependent.
Saturation of enzyme results in decreased ClH and therefore
increased Css.
4. DRUG EXCRETION
The two active processes in renal excretion of a drug that
are saturable are –
Active tubular secretion e.g. penicillin G. After saturation
of the carrier system, a decrease in renal clearance occurs.
Active tubular reabsorption e.g. water soluble vitamins
and glucose. After saturation of the carrier system, an
increase in renal clearance occurs.
Other sources of nonlinearity in renal excretion include
forced diuresis, changes in urine pH, nephrotoxicity and
saturation of binding sites.
Biliary secretion, which is also an active process, is also
subject to saturation e.g. tetracycline and indomethacin.
CAUSE OF N0N-LINEAR KINETIC & PHARMACOKINETIC
PARAMETER AFFECTED
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Non - Linear Pharmacokinetics

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CENTURION UNIVERSITY OF TECHNOLOGY AND

The rate process of a drug’s ADME are dependent upon

LINEAR PHARMACOKINETIC NON-LINEAR

 Pharmacokinetic parameter for a  Pharmacokinetic parameter for a

 Dose independent  Dose dependent

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