Biopharmaceutics Non linear pharmacokinetics

Biopharmaceutics Non linear

1. #
PRESENTEDBY:-
Gurminder Kaur
Department ofPharmaceutics,
ASBASJSMCOP,Bela.
B.Pharmacy
Subject-Biopharmaceuticsand pharmacokinetics
Subject Code-BP604T
Module-5
Non Linear Pharmacokinetics

2. 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-mentonmethod to
determine pharmacokinetic parameters.

3. CONTENTS
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Introduction
Linear & NonlinearityPharmacokinetics
Detection of non-linearity inpharmacokinetics
Causes ofnonlinearity
Michaelis –Mentenequation
Estimation of K
m andV
max
Estimation of K
m and V
max at steady-stateconcentration

4. »Attherapeuticdoses,thechangeintheamountofdrugin
thebodyorthechangeinitsplasmaconcentrationdueto
absorption,distribution,binding,metabolismorexcretion,is
proportionaltoitsdose,whetheradministeredasasingledose
orasmultipledoses.
»Insuchsituationtherateprocessesaresaidtofollwfirst
orderorlinearkineticsandallsemilogplotsofCVstfor
differentdoseswhencollectedfordoseadministered,are
superimposable.
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LINEARPHARMACOKINETICS

5. » The important pharmacokinetic parameters viz. F, K
a, K
E, Vd, Cl
R,
Cl
Hwhich describes the time course of a drug in the body
remain unaffected by thedose.
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» Pharmacokinetics is doseindependent.

6. NONLINEARPHARMACOKINETICS
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»Therateprocessofdrug’sADMEaredependuponcarrier
orenzymesthataresubstratespecific,havedefinitecapacities
andaresusceptibletosaturationatahighdrugconcentration.
»Insuchcases,anessentiallyfirst-orderkineticstransform
intoamixtureoffirst-orderandzero-orderrateprocessesand
thepharmacokineticparametersarechangedwiththesizeof
theadministereddose.
»Pharmacokineticsofsuchdrugsaresaidtobedose-
dependent.Termssynonymouswithitaremixed-order,
nonlinear and capacity-limitedkinetics.

7. DETECTION OF NON -LINEARITY IN
PHARMACOKINETICS
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•There are several tests to detect non –linearityin
pharmacokinetics but the simplest onesare:
1)First test:-Determinationofsteadystateplasma
concentrationatdifferentdoses.
2)Second test:-Determinationofsomeimportant
pharmacokinetic parameterssuch as fraction
bioavailability, elimination half lifeor total systemic
clearanceat different doses of drug. Any change in these
parameters is indicative to non-linearity which are
usuallyconstant.

8. CAUSES OFNON-LINEARITY
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•Threecauses:-I) Solubility / dissolution of drug is rate-limited;
Griseofulvin -at high concentration inintestine.
II)Carrier -mediated transport system; Ascorbic
acid -saturation of transportsystem.
III)Presystemic gut wall / hepatic metabolism
attains saturation; Propranolol.
•TheseparametersaffectedF, K
a, C
max and AUC.
•A decrease in these parameters is observed in former two causes
and an increase in latter cause.
Drugabsorption

9. #
At high doses non-linearity dueto
•Twocauses:-I) Binding sites on plasma proteins get
saturated; Phenylbutazone.
II) Tissue binding sites getsaturated.
•In both cases there is increase in plasma drug
concentration.
•Increase in V
d only in(I)
•Clearance with high ER get increased due to saturation of
bindingsites.
Drugdistribution

10. #
•Non-linearity occurs due to capacity limited metabolism, small
changes in dose administration -large variations in plasma
concentration at steady state -large intersubjectvariability.
•Two imp causes:-I) Capacity -limited metabolism -enzyme&/
cofactor saturation; Phenytoin, Alcohol.
II) Enzyme induction -decrease in plasma
concentration;Carbamazepine.
•Autoinduction in dose dependentconcentration.
•Saturation of enzymes -decrease inCl
H -increase inC
ss.
•In case of enzyme induction reversecondition.
•Other reasons includes saturation of binding sites, inhibitory
effects of the metabolites on the action ofenzymes.
Drugmetabolism

11. Drugexcretion
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•Two active processes which aresaturable,
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 alsoincreases.
Other reasons like forced diuresis, change in urine pH,
nephrotoxicity & saturation of bindingsites.
In case of biliary excretion non -linearity due to saturation -
Tetracycline &Indomethacin.

12. Examples of drugs showing nonlinearpharmacokinetics
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Causes Drugs
GIabsorption:-
Saturable transport in gut wall
Saturable GI decomposition
Intestinal metabolism
Distribution:-
Saturable plasma protein binding
Tissuebinding
Metabolism:-
Saturablemetabolism
Enzyme induction
Metabolite inhibition
Renal elimination:-
Active secretion
Tubular reabsorption
Change in urinepH
Riboflavin, Gabapentin
Penicillin G, Omeprazole
Propranolol,Salicylamide
Phenylbutazone,Lidocaine
Imipramine
Phenytion, Salicylicacid
Carbamazepine
Diazepam
Para-aminohippuric acid
Ascorbic acid, Riboflavin
Salicylic acid,Dextroamphetamine

13. MICHAELIS MENTEN ENZYME
KINETICS
It is also called as Capacity-limited metabolism orMixed
orderkinetics.
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 theproduct.
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14. #
MICHAELIS MENTENEQUATION
•The kinetics of capacity limited or saturable processes is best described by
Michaelis-Mentenequation.
-dC/dt = rate of decline of drug conc. with time
V
max = theoretical maximum rate ofthe
process
K
M = Michaelisconstant
•Three situation can now be considered depending upon the value of K
m and
C.
•
•
•
•
1)when K
M =C:
under this situation , eq I reducesto,
-dC/dt = V
max/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
dC
=
V
max .C
K
M+Cdt
Where,
……………….. I

15. #
2)If a drug at low conc. undergoes a saturable biotransformation
thenK
M>>C:
•here , K
M +C =K
M and eq. I reducesto,
-dC/dt =V
max C/K
M………………III
• above eq. is identical to the one that describe first order elimination of
drug, where V
max/K
M=K
E.
3)WhenK
M<<C:
•Under this condition ,K
M +C= C and eq. I willbecome,
-dC/dt =V
max…………….IV
above eq. is identical to the one that describe a zero order process i.e.
the rate process occurs at constant rate V
max and is independentof
drug conc.
E.g. metabolism ofethanol

16. Dc
dt
Zero order rate at highdoses
Mixed order rate at
intermediateddoses
First order rate at lowdoses
C
Figure1
A plot ofMME
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17. CALCULATION OF K
M& V
MAX
STEADY-STATECONCENTRATION
•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 = C
ssCl
T
•
If the steady-state is reached, then the dosing rate = the rateof
decline in plasma drug conc. & if the decline occurs due to a
single capacity-limited process then eq. I becomeas:
•From a plot of C
ssvs. DR, a typical curve having a shape of
hocky-stick is obtained which is shown in fig.5.
……………….. (1)
V
maxC
ss
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M
K +C
ss
DR=
……………….. (2)