Presentation By:--

B.KIRAN KUMAR

M.PHARM(PHARMACEUTICS)

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 doses or multiple doses of a drug were given.

Non linear pharmacokinetics :- Pharmacokinetic

parameters change with the size of administered dose.

Determination of steady state plasma conc. . At

different doses :- Css α dose

Determination of some of important pharmacokinetic

parameters :- t1/2 , ClT

Linear

pharmacokinetics

Non linear

pharmacokinetics

Dose independent Dose dependent

Follows 1st order rate

process

Follows combination of 1st

order and zero order rate

process

Drug Absorption :-

When absorption is solubility or 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.

-dC/dt = Vmax C / Km + C

Where,

-dC/dt = rate of decline of drug conc. With time.

Vmax = theoretical max. rate of process.

Km = michaelis constant.

Nonlinear pharmacokinetics can be best described by

Michaelis Menten Equation.

When Km = C When Km>>C

When Km<<C

_ dC = Vmax

dt 2

_ dC = Vmax.C

dt Km

- dC = Vmax

dt

Integration of Michaelis Menten Equation :-

Semi log plot of C vs. t yields a curve with terminal linear

portion, which on back extrapolation to time zero give y

intercept log Co.

log C = log Co – Vmax

2.303Km

log C = log Co + (Co –C) – Vmax

2.303Km 2.303Km

At low plasma concentration:

(Co –C)/2.303 Km = logCo/Co

A plot of 1/(dC/dt) vs. 1/ Cm of the above equation yields a straight

line with slope = Km /Vmax and y-intercept = 1/ Vmax .

Points are clustered.

1/dC/dt = Km /Vmax C + 1/ Vmax

Where,

Cm = plasma conc. At midpoint of the sampling interval.

Cm /dC/dt = Km /Vmax + Cm / Vmax

dC/dt = Vmax - (-dC/dt )Km / Cm

DR = Css ClT

Where,

F = fraction bioavailable.

X0 = oral dose .

τ = dosing interval.

DR= R0 = F X0/τ

DR = Vmax.Css

Km + Css

1/ DR = Km /Vmax Css + 1/ Vmax

DR = Vmax - Km DR /Css

A plot of DR vs. DR/ Css yields a straight line with slope –

Km and y-intercept Vmax

Apparent volume of distribution:- It is defined as the

hypothetical volume of body fluid into which a drug is

dissolved or distributed.

Real volume of distribution :- It is related to the body

water.

Body Fluid Volume % of body wt % of TBW

Vascular fluid 6 9 15

Extracellular

Fluid

12 17 28

Intracellular Fluid 24 34 57

Total Body Water 42 60 100

Physiological

fluid

compartment

Markers used Apparent volume

Plasma Evans

blue,indocyanine

green

3

erythrocytes Cr-51 2

Extra cellular fluid Raffinose, Na+,Cl-

,Br-,SO4-2

15

Total body water D2O,antipyrine 42

D.M Brahmakar,valabh prakashan,Non linear

pharmacokinetics,pg no:305-314,Distribution

of drugs ,pg no:110-113 ,second edition,2013 .

Leon Shargel ,non linear pharmacokinetics ,pg

no :177-178,sixth edition,2012.