PharmacokineticsIII

“Pharmacokinetic parameters”
MBBS-Y1, Sem2, 2020

Prof. Dr Abel Baset Taher 1

• Learning Objectives
− Define apparent volume of distribution and
show its significance
− Define bioavailability and compare oral and IV
bioavailability
− Discuss factors which affect bioavailability
− Define and compare first order kinetic and
zero order kinetic
− Define plasma half life and show its
significance

Prof. Dr Abel Baset Taher 2

Apparent volume of distribution (Vd)
• Drugs are usually distributed throughout the
body according to their affinities for the different
tissues and body compartments hypothetically, if
the body was considered to consist of only one
big fluid compartment and that the total amount
of drug M would be uniformly distributed in that
compartment such that it would have the same
concentration as in plasma C, then
Vd = M (mg)  amount of drug
C (mg/L)  conc. Of drug in plasma

3
Cont…
• Also, Vd represents the relationship
between the dose and the resulting
plasma concentration of the drug:
Vd= IV dose / plasma concentration

• E.g. for aminophylline, if the dose is

350mg and plasma concentration is
10mg/L
So Vd=350 ÷ 10 = 35 L

4
Significance of Vd:
1.It is an estimate of the extent of extravascular tissue
uptake of drugs
− Small Vd e.g. frusemide (7.7L) indicates very low tissue
uptake
− Large Vd e.g. digoxin (500L) indicates extensive tissue
distribution
2.In case of toxicity
• Dialysis is not useful for drugs with large Vd
• Dialysis is useful for drugs with low Vd (most of the drug
in circulation)
3.Vd is important to calculate size of loading dose:
LD= Vd × Css
4.Vd is directly proportionate to half life and inversely
proportionate to the elimination rate of the drug 5
 Bioavailability
Definition:
It is the percentage of the dose that reaches the
systemic circulation after administration via
stated route.
− The bioavailability of any drug after IV
administration is 100%, while it is frequently less
than 100% after oral administration. Accordingly,
the problems regarding bioavailability refer to
oral administration.
− Examples for drugs having variable
bioavailability include digoxin and phenytoin.
6
Oral bioavailability =AUC (oral) / AUC (IV) x 100
Where AUC is area under curve

Factors affecting bioavailability:

1-Factors affecting absorption
2- First pass metabolism

Bioequivalence: occurs when 2 forms of the

same drug have the same bioavailability and
the same rate of absorption.

7
First order kinetics:
Definition:
Most of the drugs exhibit first order kinetic in which
the rate of drug elimination is proportional to the
plasma drug concentration.

− Elimination rate of drugs= plasma drug conc. x drug clearance

− The elimination rate declines as the plasma conc.
declines.
− Elimination half life (t½) remains constant.
− Time required to reach Css is about 4-5 times the t
½.
8
Zero order kinetics:
Definition:
Few drugs such as ethanol exhibit zero order
kinetic in which the rate of drug elimination is
constant and is independent of plasma drug conc.

− This is because the capacity of metabolizing

enzymes and carrier systems responsible for drug
elimination is very limited.
− Elimination half life (t ½) is proportional to plasma
drug conc.
− Time required to reach Css is unpredictable.

9
Saturable kinetics:
− Some drugs as phenytoin, salicylates
and theophylline follow first order
kinetics in low concentrations and zero
order kinetics at higher concentrations.

Prof. Dr Abel Baset Taher 10

Prof. Dr Abel Baset Taher 11
Elimination half life
− It is the time required to eliminate 50% of the
drug in the body or to reduce the plasma drug
conc. by 50%.

Elimination half life (t ½) = 0.693 Vd / clearance

Prof. Dr Abel Baset Taher 12

Significance of half life:
1.It indicates time required to reach Css.
− Steady state concentration (Css): is the
concentration of the drug when the rate of
input (absorption) equals the rate of output
(elimination) of the drug.
− For most drugs (1st order kinetics) Css is
reached after 4-5 t 1/2 following repeated
administration every half life.

Prof. Dr Abel Baset Taher 13

2. It determines the dosage interval.
− For most drugs inter- dose fluctuations in
blood level are acceptable when the dosage
interval equals t 1/2.
3. It is an index of drug clearance or
elimination provided that Vd is constant
Clearance = 0.693 Vd / t 1/2

Prof. Dr Abel Baset Taher 14

Drug clearance
It is the volume of body fluid from which a
substance is removed per unit time.
Total clearance:
it is the sum of the renal clearance, hepatic
clearance, pulmonary clearance and any other
clearance.
− Clearance = 0.693 Vd / t 1/2
− Drug clearance represents that fraction of
Vd from which drug is eliminated.

Prof. Dr Abel Baset Taher 15

Renal clearance =
Renal excretion rate÷ plasma drug concentration

− Drugs that are eliminated primarily by glomerular

filtration with little tubular secretion or reabsorption
will have renal clearance that is approximately
equal to the creatinine clearance =100ml/min.
− If the renal drug clearance> creatinine clearance,
this indicates that drug undergoes tubular secretion.
− If the renal drug clearance< creatinine clearance,
this indicates:
1. The drug is highly bound to plasma protein
2. The drug undergoes passive reabsorption from renal
tubules.
16
Loading dose
− Is the dose which can raise the concentration
of drug in plasma to the target concentration.
− It is used if we need to reach Css very rapidly
as in emergency e.g. digoxin in acute heart
failure.
− Loading dose = Vd x desired concentration (Css).
− Unexpected toxicity can occur.

Prof. Dr Abel Baset Taher 17

Maintenance dose
− Is the dose which aims at maintaining a
desired steady state concentration.
− Maintenance dose = Cl x Css x Tm
Cl = clearance Tm = dose interval

Dosing accumulation:
− Drug will accumulate in the body until dosing
stop.
− If dosing interval is shorter than 4 t1/2
accumulation will be detected.

18
 Thank you

Prof. Dr Abel Baset Taher 19