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RELATIONSHIP OF PLASMA
DRUG-PROTEIN BINDING TO
DISTRIBUTION AND ELIMINATION

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 CONTENTS
• Introduction
• Relationship between Vd and drug elimination half-life
• Clinical examples
1) Drugs with large Vd and a long elimination t1/2
2) Drugs with small Vd and a long elimination t1/2
Clearance
• Elimination of protein bound drugs:
restrictive versus non-restrictive elimination
• Clinical example of diazepam

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 PART 1
Introduction
&
Relationship between vd and drug
elimination half-life

FATIMA SHADAB
17302

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Relationship of Plasma Drug Protein Binding to
Distribution and Elimination
INTRODUCTION:

• Highly bound Drugs : reduced overall drug clearance.

• For a drug that is metabolized mainly by the liver,
binding to plasma proteins prevents the drug from
entering the hepatocytes, resulting in reduced drug
metabolism by the liver.
• Bound drugs may not be available as substrates for liver
enzymes.
• Protein bound drug as larger molecule cannot diffuse
easily in glomeruli.
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• The elimination half-life increase when percent of drug
bound to plasma protein increases. E.g. Cephalosporin
(excreted by both renal and biliary secretion.)
• The half life of such drug which are excreted in bile do
not correlates with the extent of plasma protein
binding.
• Drug protein binding usually measured in plasma and
serum.
• On other hand, a drug that is extensively bound and
actively secreted by kidneys have short elimination
half-life. E.g. Penicillin.

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 Relationship between VD and Drug
Elimination Half-life
• Drug elimination is mainly by renal and other
metabolic processes.
• Extensive drug distribution has the effect of
diluting the drug in large volume making it harder
for kidneys to filter the drug.
• T1/2 of the drug is prolonged if clearance is
constant and VD is increased.
• Cl= kVD
• T1/2= 0.693 VD/Cl
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Low plasma drug concentration resulted
from:

1. Extensive distribution into tissues

2. Extensive distribution into peripheral
tissues
3. Lack of plasma drug protein binding

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 PART 2
CLINICAL EXAMPLES

KINZA FAZAL
16229

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 Drugs with large volume of
distribution and a long elimination t1/2
MACROLIDE- Dirithromycin

 Extensively distribution
 Large steady state volume of distribution of about
800L.
 Elimination t1/2 44 hours
 Large total body clearance of 226 - 1040mL/min
(13.6 - 62.4 L/hrs.)
 OD dosing
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 So,
Clearance is large due to:
1) large volume of distribution
2) k is relatively small.
 Clearance is large but:
elimination half-life is long because of large VD.
 Drug take long time to be removed when the drug
is distributed extensively over a large volume
despite a large clearance,
t1/2 accurately describes drug elimination alone. 

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Drugs with small volume of distribution
and a long elimination t1/2
Tenoxicam
 NSAID
 Plasma protein binding 99%
 Very polar - penetrates cell membranes slowly.
 Poorly distributed to tissues:
apparent volume of distribution 9.6L
 Low total plasma clearance - 0.106L/h
 Elimination half-life - 67 hours
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 Clearance
Cl= kVD
 This relationship is consistent with small Cl and small VD
observed for tenoxicam.
t½=0.693 VD/Cl
 Cl is clearly affected by Vd & many variables in biological
factors
 Actual elimination half-life is long:
because the plasma tenoxicam clearance is so low that it
dominates in this equation.
 Due to restrictive drug clearance drug not clear rapidly.

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 PART 3
ELIMINATION OF PROTEIN BOUND
DRUGS:
RESTRICTIVE VS NON-RESTRICTIVE
SUNDAS
16536

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 RESTRICTIVE VS NON-RESTRICTIVE
ELIMINATION
Restrictive Elimination
• When a drug is tightly
bound to a protein only the
unbound drug is assumed
to be metabolized: drug
belonging to this category
are described as
restrictively eliminated.
• Protein Binding impedes
elimination process
• Drugs are slowly eliminated
Non-Restrictive Elimination
• Drugs (some) may be
eliminated even when they
are protein bound; drugs in
thus category are described
as non-restrictively
eliminated.
• Protein Binding does not
impedes elimination process
• Drugs are normally rapidly
eliminated
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 RESTRICTIVE VS NON-RESTRICTIVE
ELIMINATION
Restrictive Elimination
Influence of protein binding
• Exist a relationship
• Elimination is affected
(analogous situation to
glomerular filtration)
• Half life affected
• Serious dosage
miscalculations
• Free drug concentration
may not change
Non-Restrictive Elimination
Influence of protein binding
• Less influence
• Elimination not affected
• Half life not affected
(analogous situation to
active tubular secretion.)
• Serious dosage
miscalculation
• Free drug diffusion may be
affected by a change in free
fraction
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 RESTRICTIVE VS NON-RESTRICTIVE
ELIMINATION
Restrictive Elimination Non-Restrictive Elimination
So whether a drug is restrictively or non-restrictively
eliminated must be considered when determining the role of
change in protein binding

EXAMPLES: EXAMPLE:
• Cephalosporins • Morphine
• Quinidine • Metoprolol
• Tolbutamide • Propranolol
• Warfarin` • Para-aminohippacuric acid

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 Molecular effect of protein binding on
elimination, not always predictable in practice
Restrictive Elimination Non-Restrictive Elimination
Such drugs have: Such drugs have:
• Extensive protein binding and very • No effect of protein binding
small plasma • High hepatic ER then their unbound
(clearance Cl (h)= fu x Clint) fraction in plasma (ER > fu)
• Generally smaller hepatic ER then their • Therefore, hepatic elimination is non-
unbound fraction in plasma (ER < fu) restrictive
• Therefore, Hepatic elimination is
EXAMPLES:
restrictive
• Propranolol
EXAMPLES:
• Warfarin & a series of NSAIDs their
• Phenylbutazone
a)elimination is hepatic
• Oxicams icluding;
b)BA from is complete
-Piroxicam
c) not undergo enterohepatic
-isoxicam
circulation
-tenoxicam
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 EXAMPLES OF DRUGS METABOLIZING
RESTRUCTIVELYB & NON-RESTRICTIVELY
• Warfarin and Diazepam • Propranolol:
- Protein bound = 99%& - Protein bound = 89%
98% - Unbound = 11%
- Unbound = 1% & 2% - Low bioavailability
- ER= Low - ER = 0.7-0.9 High
- lipophilic property - Short elimination half
- Half life = 37 hours life

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 PART 4

MEHWISH IJAZ
16232

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 CLINICAL EXAMPLE
Diazepam has an average elimination half life of
37 hours and Vd of 77 L and is mainly eliminated
by demethylation.

• Question arise,
Is diazepam slowly eliminated due to the
extensive binding to protein, a large Vd or simply
because diazepam has a slow metabolic rate(0r
low extraction ratio)?
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 REASONS
• There are multiple factors that are responsible for longer
t-half of diazepam.
 Protein binding
 Diazepam demethylation(Genetic polymorphism), T-
half=20 to 84 hours Clearance=2.8±0.9mL/min(slow
metabolizer), and 19.5±9.8mL/min (fast metabolizer)
 Slow metabolism is the main cause for longer elimination
half life
 The longer half life due to small ER in some subjects
 Larger elimination due to large volume of distribution

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• As Diazepam is highly protein bound drug which
is one of the reason for small clearance and long
T-half of metabolism.
• Schmidt et al discuss various situations that may
cause changes in half life as a result of changes in
protein-drug binding. He concluded that:
“Plasma protein binding can have multiple effects
on the pharmacokinetics and pharmacodynamics
of a drug and simple, generalized guideline for the
evaluation of clinical significance of protein binding
frequently cannot be applied”
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 REFERENCES
• Leon Shargel, Andrew B.C. Yu, Seventh Edition,
Applied Biopharmaceutics and
Pharmacokinetics, Maryland
• Milo Gibaldi, (1984), Biopharmaceutics and
Clinical Pharmacokinetics, (4th Edition), Lea &
Febiger

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THANK YOU

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