Non linear pharmacokinetics and different volumes of distribution
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Transcript of Non linear pharmacokinetics and different volumes of distribution
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.