causes of non-linearity

1. Nonlinear
pharmacokinetics causes
of non-linearity
Presented by
Amartya Nandi
M.Pharm (Pharmceutics)
2023001515

2. Contents
• Introduction
• Difference
• Characteristics
• Detection
• Causes of nonlinearity
• Examples

3. Introduction
The rate process of drug's ADME are dependent upon carrier or enzymes that are
substrate specific, have definite capacities and are susceptible to saturation at a 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 are changed with the
size of the administered dose.
Pharmacokinetics of such drugs are said to be dose- dependent. Terms synonymous with
it are mixed-order, nonlinear and capacity-limited kinetics.

4. Differentiation between Linear and
Nonlinear Kinetics
• Linear: if the dose is increased, the plasma
concentration or area under the plasma
concentration-time curve (AUC) will be
increased proportionally
• Nonlinear kinetics (or dose-dependent
kinetics): the kinetic parameters, such as
clearance, volume of distribution, and half
life, may vary depending on the
administered dose.

5. Drugs that demonstrate saturation kinetics
usually show the following characteristics
Elimination of drug does not follow simple first-order kinetics that is elimination kinetics
are nonlinear.
The elimination half-life changes as dose is increased. Usually, the elimination half-life
increases with increased dose due to saturation of an enzyme system. However, the
elimination half-life might decrease due to "self"-induction of liver biotransformation
enzymes, as is observed for carbamazepine.
The area under the curve (AUC) is not proportional to the amount of bioavailable drug.
The saturation of capacity-limited processes may be affected by other drugs that require
the same enzyme or carrier-mediated system (i.e., competition effects).
The composition and/or ratio of the metabolites of a drug may be affected by a change in
the dose.

6. Detection of non-
linearity in
pharmacokinetics
There are several tests to detect non-
linearity in pharmacokinetics, but the
simplest ones are:
• First test:- Determination of steady state
plasma concentration at different doses.
• Second test:- Determination of some
important pharmacokinetic parameters
such as fraction bioavailability,
elimination half life or total systemic
clearance at different doses of drug. Any
change in these parameters is indicative to
non-linearity which are usually constant.

7. Causes of
nonlinearity
Drug Absorption
Three causes:-
• Solubility / dissolution of drug is rate-limited; Griseofulvin
- at high concentration in intestine.
• Carrier - mediated transport system; Ascorbic acid -
saturation of transport system.
• Pre-systemic gut wall / hepatic metabolism attains
saturation; Propranolol.
These parameters affected F, Ka, Cmax and AUC.
A decrease in these parameters is observed in former two
causes and an increase in latter cause.

8. At high doses non-linearity due to
Two causes:-
• Saturation of Binding sites on plasma proteins;
Phenylbutazone.
• Saturation of Tissue binding sites.
In both cases there is increase in plasma drug
concentration.
Increase in Vd only in binding site
Clearance with high ER get increased due to
saturation of binding sites.
Drug distribution

9. Drug metabolism
Non-linearity occurs due to capacity limited metabolism, small changes in dose
administration - large variations in plasma concentration at steady state - large
intersubject variability.
Two important causes:-
• Capacity - limited metabolism - enzyme &/ cofactor saturation; Phenytoin, Alcohol.
• Enzyme induction - decrease in plasma concentration; Carbamazepine.
Autoinduction in dose dependent concentration.
Saturation of enzymes - decrease in Clh increase in Css.
In case of enzyme induction reverse condition.
Other reasons includes saturation of binding sites, inhibitory effects of the
metabolites on the action of enzymes.

10. Drug excretion
Two active processes which are saturable,
• Active tubular secretion - Penicillin G
• Active tubular reabsorption - Water soluble vitamins & Glucose.
Saturation of carrier systems - decrease in renal clearance in case of tubular
secretion & increase in tubular reabsorption. Other reasons like forced diuresis,
change in urine pH, nephrotoxicity & saturation of binding sites.
In case of biliary excretion non - linearity due to saturation - Tetracycline &
Indomethacin.

11. Drugs showing nonlinear pharmacokinetics
GI absorption:-
Saturable transport in gut wall Riboflavin, Gabapentin
Saturable GI decomposition Penicillin G, Omeprazole
Intestinal metabolism Propranolol, Salicylamide
Distribution:-
Saturable plasma protein binding Phenylbutazone, Lidocaine
Tissue binding Imipramine

12. Metabolism:-
Saturable metabolism Phenytion, Salicylic acid
Enzyme induction Carbamazepine Diazepam
Metabolite inhibition Para- aminohippuric acid
Renal elimination:-
Active secretion Ascorbic acid, Riboflavin
Tubular reabsorption Salicylic acid,
Change in urine Ph Dextroamphetamine

13. References
1. Biopharmaceutics and Pharmacokinetics a treatise by Brahmankar DM, Jaiswal
SB.
2. Biopharmaceutics & pharmacokinetics by Dr. Shobha Rani R. Hiremath.