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