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Pharamcokinetics: Course In-Charge: Nimra Waheed Course Name: Biopharmaceutics and Pharmacokinetics Course Code: 613-T

The document discusses linear and non-linear pharmacokinetics. It provides examples of how drug absorption, distribution, metabolism and excretion can demonstrate non-linear kinetics when the processes become saturated. This can occur through saturation of protein binding sites, enzyme systems, or transport mechanisms. The Michaelis-Menten equation is presented as a way to describe non-linear pharmacokinetics mathematically. Reference books on pharmacokinetics and related topics are also listed.

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Neha Gulfam
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171 views21 pages

Pharamcokinetics: Course In-Charge: Nimra Waheed Course Name: Biopharmaceutics and Pharmacokinetics Course Code: 613-T

The document discusses linear and non-linear pharmacokinetics. It provides examples of how drug absorption, distribution, metabolism and excretion can demonstrate non-linear kinetics when the processes become saturated. This can occur through saturation of protein binding sites, enzyme systems, or transport mechanisms. The Michaelis-Menten equation is presented as a way to describe non-linear pharmacokinetics mathematically. Reference books on pharmacokinetics and related topics are also listed.

Uploaded by

Neha Gulfam
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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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PHARAMCOKINETICS

COURSE IN-CHARGE: NIMRA WAHEED


COURSE NAME: BIOPHARMACEUTICS
AND PHARMACOKINETICS
COURSE CODE: 613-T
LEARNING OBJECTIVES
• Introduction,
• Linear and Non-linear Pharmacokinetics
• Application of pharmacokinetics in clinical situations
PHRMACOKINETIC
S

Pharmacokinetics is defined as the kinetics of drug absorption, distribution,


metabolism and excretion (KADME) and their relationship with the
pharmacological, therapeutic or toxicological response in man and animals.
 Use of pharmacokinetic principles in optimizing the drug dosage for
individual patient in order to achieving maximum therapeutic utility is
called as clinical pharmacokinetics.

 There are two aspects of pharmacokinetic studies –


1.Theoretical aspect – which involves development of pharmacokinetic
models to predict drug disposition after its administration. Statistical methods
are commonly applied to interpret data and assess various parameters.

2.Experimental aspect – which involves development of biological sampling


techniques, analytical methods for measurement of drug (and metabolites)
concentration in biological samples and data collection and evaluation.
Common units in Pharmacokinetics
S.no Pharmacokinetic parameter Abbreviation Fundamental units Units example
1. Area under the curve AUC Concentration x time µg x hr/mL
2. Total body clearance ClT Volume x time Litres/time
3. Renal clearance ClR Volume x time Litres/time
4. Hepatic clearance ClH Volume x time Litres/time
5. Apparent volume of distribution VD Volume Litres
6. Vol. of distribution at steady state VSS Volume Litres
7. Peak plasma drug concentration CMAX Concentration mg/L
8. Plasma drug concentration CP Concentration mg/L
9. Steady-state drug concentration Css Concentration mg/L
10. Time for peak drug concentration TMAX Time Hr
11. Dose DO Mass mg
12. Loading dose DL Mass mg
13. Maintenance dose DM Mass mg
14. Amount of drug in the body DB Mass Mg
15. Rate of drug infusion R Mass/time mg/hr
16. First order rate constant for drug absorption Ka 1/time 1/hr
17. Zero order rate constant for drug absorption KO Mass/time mg/hr
18. First order rate constant for drug elimination K 1/time 1/hr
19. Elimination half-life t Time hr
 Pharmacokinetics :- It is defined as the kinetics of drug
absorption, distribution ,metabolism and excretion
and their relation ship with the pharmacological
,therapeutic or toxicological response in man and
animals.

 Linear pharmacokinetics :- Pharmacokinetic


parameters for a drug would not change when
different dosesor multiple doses of a drug were given.

 Non linear pharmacokinetics :- Pharmacokinetic


parameters change with the size of administered dose.
NON-LINEAR
BINDING
A limited number of sites exist on plasma proteins. Average plasma concentration of albumin is
43g/L or 600 mm. the sites to which drugs bind in the tissue may be similarly limited.
Consequently, the volume of distribution depends on drug concentrations, a concentrate-
dependent behaviour.

Let us consider a hypothetical situation wherein 2 drugs are given by an I.V. bolus in
equal pl
doses. One drug is 90% protein bound whereas the other drug does not bind to the
asma protein and both are eliminated solely by glomerular filtration through the kidney.

Plasma Drug A
drug
level

Time in hrs
Plasma drug level – time profile of two drugs given in equal
18
doses
In the above plot drug A represents 90% bound to plasma protein,
curve B represents a drug not bound to plasma protein.

The protein bound drug is more concentrated in plasma than the drug
that is
low and hence, its elimination rate will be slow when compared with the drug that
does not bind to plasma protein. Further, the protein bound drug shows a non-linear
elimination whereas the drug that is not bound to the plasma protein shows a linear
elimination.

19
A careful elimination of curve A reveals that the slope of the bound
drug decreases gradually as the drug concentration decreases. It means that
the free drug concentration decreases and bound drug concentration increases as the
total drug concentration in plasma decreases. In other words, the ratio of the bound
drug to free drug is not constant but increases at a low plasma concentration of the
drug. Therefore, fitting the plasma concentration-time data of a protein-bound drug
into a simple one compartment model without accounting for protein binding results
in an erroneous estimation of volume of distribution & half life.

Drugs which are bound to plasma proteins will show


non-linear
kinetic

20
NON-LINEARITY OF PHARMACOLOGICAL
RESPONSES

 The empirical approach in optimization of drug therapy was based on relating


pharmacological response to the dose administered. Given dose or dosing rate can result
in large deviations in plasma drug concentration which in most cases are attributable to
formulation factors, pharmacokinetics and pharmacological response.

 Sometimes the pharmacological response may be non-linear due to –

 saturable absorption

 saturable binding or reabsorption

 Saturable elimination

21
 Drug Absorption :-
 When absorption is dissolution rate limited Ex:-
Griseofulvin.
 When absorption involves carrier mediated transport system
Ex:-absorption of riboflavin ,ascorbic acid,cyanocobalamine .
 When presystemic gut wall or hepatic metabolism attains
saturation
Ex:- propranalol ,hydralazine and verapamil.
 Changes in gastric emptying and GI blood flow also cause
nonlinearity.
 Drug Distribution :-
 Saturation of binding sites on plasma proteins Ex:- Phenyl
butazone.
 Saturation of tissue binding sites Ex:- Thiopental.

 Drug Metabolism :-
 Capacity limited metabolism due to enzyme or cofactor
saturation Ex:-phenytoin.
 Enzyme induction Ex:-carbamazepine.
Saturation of binding sites ,inhibitory effect of the
metabolite on enzyme and pathological situations
and changes in hepatic blood flow.
 Drug Excretion :-
 Active tubular secretion Ex:- penicillin G.
 Active tubular reabsorption Ex:- Glucose and water
soluble vitamins.
 Forced diuresis,changes in urine pH,nephrotoxicity and
saturation of binding sites.
 Nonlinear pharmacokinetics can be best described by
Michaelis Menten Equation.

-dC/dt = Vmax C / Km + C
 Where,
-dC/dt = rate of decline of drug conc. With time.
Vmax = theoretical max. rate of process.
= michaelis constant.
Km
SUMMARY
• We have discussed linear and non-linear pharmacokinetics.
• We have discussed the concept, and its application in clinical studies.
REFERENCE BOOKS
• Biopharamaceutics and Clinical pharmacokinetics by Milo Gibaldi
• Applied biopharmaceutics and pharmacokinetics Textbook by Leon Shargel
• Pharmacokinetic-pharmacodynamic modeling and simulation Book by Peter L. Bonate
• Essentials of Biopharmaceutics and Pharmacokinetics Book by Ashutosh Kar
• Pharmacokinetics: Principles and Applications by Mehdi Boroujerdi
• Basic Pharmacokinetics by Mohsen A. Hedaya
• Clinical Pharmacokinetics: Concepts and Applications by Malcolm Rowland, Thomas N.
Tozer
• Biopharmaceutics and Pharmacokinetics Book by A. P. Pawar and J. S. Kulkarni

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