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Unit-5 BP

This document discusses non-linear pharmacokinetics. It begins by defining linear and non-linear pharmacokinetics, and describes how non-linearity can be detected by changes in pharmacokinetic parameters at different doses. Non-linearity can be caused by saturation of absorption, distribution, metabolism or excretion processes. The Michaelis-Menten equation is introduced to model capacity-limited or saturable processes, and methods for estimating kinetic parameters Km and Vmax using steady-state drug concentrations are presented. Examples of drugs exhibiting non-linear pharmacokinetics due to different causes are also provided.

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2K views18 pages

Unit-5 BP

This document discusses non-linear pharmacokinetics. It begins by defining linear and non-linear pharmacokinetics, and describes how non-linearity can be detected by changes in pharmacokinetic parameters at different doses. Non-linearity can be caused by saturation of absorption, distribution, metabolism or excretion processes. The Michaelis-Menten equation is introduced to model capacity-limited or saturable processes, and methods for estimating kinetic parameters Km and Vmax using steady-state drug concentrations are presented. Examples of drugs exhibiting non-linear pharmacokinetics due to different causes are also provided.

Uploaded by

TanyaMishra
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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B.

Pharmacy
Subject-Biopharmaceutics and pharmacokinetics
Subject Code-BP604T

Module-5
Non Linear Pharmacokinetics

PRESENTED BY:-
Gurminder Kaur
Department of Pharmaceutics,
ASBASJSMCOP,Bela.
#
Objective of course:
Understand various pharmacokinetic parameters, their
significance and application.

Learning Outcomes:
Students will learn about various factors causing non
linear pharmacokinetics and tests to detect non linearity.
Students will learn about Michaelis-menton method to
determine pharmacokinetic parameters.
CONTENTS

Introduction

Linear & Nonlinearity Pharmacokinetics

Detection of non-linearity in pharmacokinetics

Causes of nonlinearity

Michaelis – Menten equation

Estimation of Km and Vmax

Estimation of Km and Vmax at steady-state concentration


#
LINEAR PHARMACOKINETICS

» 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 situation the rate processes are said to follw first


order or linear kinetics and all semilog plots of C Vs t for
different doses when collected for dose administered, are
superimposable.

#
» The important pharmacokinetic parameters viz. F, Ka, KE, Vd, ClR,
ClH which describes the time course of a drug in the body
remain unaffected by the dose.

» Pharmacokinetics is dose independent.

#
NONLINEAR PHARMACOKINETICS

» The rate process of drug’s ADME are depend 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.

#
DETECTION OF NON-LINEARITY IN
PHARMACOKINETICS
• There are several tests to detect non –linearity in
pharmacokinetics but the simplest ones are:

1) First test:- Determination of steady state plasma


concentration at different doses.

2) 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.
#
CAUSES OF NON-LINEARITY
Drug absorption

• Three causes:- I) Solubility / dissolution of drug is rate-limited;


Griseofulvin - at high concentration in intestine.

II) Carrier - mediated transport system; Ascorbic


acid - saturation of transport system.
III)Presystemic gut wall / hepatic metabolism
attains saturation; Propranolol.

• These parameters affected F, Ka, Cmaxand AUC.

• A decrease in these parameters is observed in former two causes


and an increase in latter cause.
#
Drug distribution
At high doses non-linearity due to
• Two causes:- I) Binding sites on plasma proteins get
saturated; Phenylbutazone.

II) Tissue binding sites get saturated.

• In both cases there is increase in plasma drug


concentration.

• Increase in Vdonly in (I)

• Clearance with high ER get increased due to saturation of


binding sites. #
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 imp causes:- I) Capacity - limited metabolism - enzyme &/


cofactor saturation; Phenytoin, Alcohol.

II) 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.
Drug excretion
• Two active processes which are saturable,
I) Active tubular secretion - Penicillin G
II) Active tubular reabsorption - Water soluble
vitamins & Glucose.

• Saturation of carrier systems - decrease in renal clearance in


case of I & increase in II. Half life also increases.
• 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.

#
Examples of drugs showing nonlinear pharmacokinetics
Causes Drugs
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
Metabolism:-
Saturable metabolism Phenytion, Salicylic acid
Enzyme induction Carbamazepine
Metabolite inhibition Diazepam
Renal elimination:-
Active secretion Para- aminohippuric acid
Tubular reabsorption Ascorbic acid, Riboflavin
Change in urine pH Salicylic acid, Dextroamphetamine
#
MICHAELIS MENTEN ENZYME
KINETICS

It is also called as Capacity-limited metabolism or Mixed


order kinetics.

E+D ED E + M

Enzymes usually react with the substrate to form enzyme


substrate complexes; then the product is formed. The
enzyme can go back to react with another substrate to
form another molecule of the product.

#
MICHAELIS MENTEN EQUATION
• The kinetics of capacity limited or saturable processes is best described by
Michaelis-Menten equation.

dC Vmax . C
= ……………….. I
dt KM+ C
Where ,
-dC/dt = rate of decline of drug conc. with time
Vmax= theoretical maximum rate of the
process
KM= Michaelis constant

• Three situation can now be considered depending upon the value of Kmand
C.
1) when KM= C:
under this situation , eq I reduces to,
• -dC/dt = Vmax/2...................II
• The rate of process is equal to half of its maximum rate.
• This process is represented in the plot of dc/dt vs. C. shown in fig. 1 #
•
2) If a drug at low conc. undergoes a saturable biotransformation
then KM>>C:

• here , KM+C =KMand eq. I reduces to,

-dC/dt =VmaxC /KM………………III

• above eq. is identical to the one that describe first order elimination of
drug, where Vmax/KM= KE.

3) When KM<<C:
• Under this condition ,KM+C= C and eq. I will become,
-dC/dt =Vmax…………….IV

above eq. is identical to the one that describe a zero order process i.e.
the rate process occurs at constant rate Vmaxand is independent of
drug conc.
E.g. metabolism of ethanol #
Zero order rate at high doses
Mixed order rate at
intermediated doses
Dc First order rate at low doses

dt
C

Figure 1
A plot of MME

#
CALCULATION OF KM & VMAX
STEADY- STATE CONCENTRATION
• If drug is administered for constant rate IV infusion/ in a multiple
dosage regimen, the steady-state conc. is given in terms of
dosing rate (DR):
DR = CssClT ……………….. (1)

• If the steady-state is reached, then the dosing rate = the rate of


decline in plasma drug conc. & if the decline occurs due to a
single capacity-limited
Vmax Css
process then eq. I become as:
DR = K + C ……………….. (2)
M ss

• From a plot of Css vs. DR, a typical curve having a shape of


hocky-stick is obtained which is shown in fig. 5.
#

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