Pharmacokinetics: Drug Distribution

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Pharmacokinetics Drug Distribution
Topic 3
713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY Dr.
Korawuth Punareewattana
Faculty of Veterinary Medicine, Khon Kaen
University
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Topic Contents

• Definition
• Factors affecting drug distribution
• Volume of distribution
• Phase of distribution
• Protein binding
• Drug reservoir
• Drug redistribution

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Pharmacokinetics Drug distribution

• Drug distribution
• is a step which describes the reversible transfer
  of drug from one location to another within the
  body.
• Distribution is influenced by
• a) Blood flow to target tissues
• b) Ability of drug to exit blood vessels
• typical capillary - no barrier
• blood-brain barrier tight junctions between
  endothelial cells (only lipid soluble)
• placental barrier - only lipid soluble pass
  freely
• c) Ability to enter cells
• must be lipid soluble, or have transporter
• most drugs act at receptors on cell surface (do
  not enter)

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Factors affecting drug distribution

• Factors ? rate of distribution
• (how fast)
• Membrane permeability
• Blood perfusion
• Factors ? extend of distribution (how much)
• Lipid solubility
• pH pKa
• Protein binding
• Plasma protein binding
• Tissue protein binding
• Elimination processes

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Drug distribution and Body water
Total body water
plasma volume
extracellular
plasma
3 liters 5
interstitialvolume
interstitial volume
15 liters 25
intracellularvolume
intracellular
12 liters 20
42 liters 70
Water composition in 60 Kg Body Weight
27 liters 45
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Drug distribution and Body water
cell
Intra-vascular
Interstitial
Intra-cellular
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Drug distribution and Body water
cell
Distribution - Evans Blue Intra-vascular space
only
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Drug distribution and Body water
cell
Distribution Inulin Extracellular water
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Drug distribution and Body water
cell
Distribution Ethanol All water
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Drug distribution and Body water
cell
Distribution Quinacrine Concentration into
cells
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Volume of Distribution (Vd)

• A measure of the tendency of a drug to move out
  of the blood plasma to some other site.
• Or A measure of extend of distribution

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Volume of Distribution (Vd)
How can we measure the extent of distribution?
Apparent volume of distribution (Vd)
VOLUME OF DISTRIBUTION FOR SOME DRUGS
DRUG Vd (L) cocaine
140 clonazepam 210 amitriptyline
1050 amiodarone 5000
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Volume of distribution
C D/V V D/C
D
V
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Volume of distribution - an example
D 50 mg C 2.5 mg/L V D/C 50mg /
2.5mg/L 20 Litres
D
V
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What is the volume of water in the beaker?
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What is the volume of water in the beaker?
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Volumes of distribution (Vd)(In litres for
average 70 Kg adult human)
Warfarin 7 Gentamicin
16 Theophylline 35 Cimetidine
140 Digoxin 510 Mianserin
910 Quinacrine 50,000
Small vol. Mainly stays in plasma little in
tissues.
Medium vol. Similar concs in plasma and tissues
Large vol. Mainly in tissues, little in plasma.
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Volume of distribution and body weight
Vd depends upon body size. May be quoted as L/kg
(Litres per kg body weight) e.g. Theophylline
Vd 0.48 L/kg For 60 kg adult, Vd 0.48
L/kg x 60 kg
28.8 L
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Practice calculation
A dose of analgesic (50mg) is administered i.v.
and a blood sample is taken shortly afterwards.
The initial concentration of analgesic in the
blood sample is 0.85 µg.ml-1. Calculate the
volume of distribution of the analgesic (in
Litres).
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Model solution
Mixed units!
V D/C0 50 mg / 0.85 µg.ml-1 50,000
µg / 0.85 µg.ml-1 58,824 ml 59
Litres Take home message UNITS ... UNITS ...
UNITS ...
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Phases of Distribution
First phase reflects cardiac output and regional
blood flow. Thus, heart, liver, kidney brain
receive most of the drug during the first few
minutes after absorption. Second phase Delivery
to muscle, most viscera, skin and adipose is
slower, and involves a far larger fraction of the
body mass.
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Blood flows
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Two compartments model
Drug penetrates some tissues rapidly and others
slowly. Combine blood and rapid tissues (T1 T2)
as first compartment. Drug spreads instantly
through this compartment. Combine slow tissues
(T3 T4) as second compartment.
T1
Blood
T4
T2
T3
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Drug Reservoirs
Body compartments that a drug can accumulate in
serve as reservoirs. They have dynamic effects
on drug availability.

• Plasma reservoirs
• Albumin
• a1-acid glycoprotein

• Tissue or Cellular reservoirs
• Adipose reservoir
• Bone reservoir
• Transcellular reservoir
• GI tract reservoir

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Pharmacokinetics
Locus of actionreceptorsBound Free
TissuereservoirsBound Free
Systemiccirculation
Absorption
Excretion
Free drug
Bound drug
Metabolites
Biotransformation
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Protein Binding
Passive (not active) transport of drugs across
biological membranes is influenced by protein
binding. Binding may occur - with plasma
proteins or - with non-specific tissue proteins
in addition to the drugs receptors. Only
drug that is not bound to proteins (i.e., free or
unbound drug) can diffuse across membranes
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• Protein binding
• not only affects the activity of the drug (bound
  inactive)
• But also can influence its distribution from one
  compartment to another.
• This is particularly true with respect to
  glomerular filtration and passive transport.
• Free Protein ? Bound Drug Drug

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Plasma
Extracellular water
Plasma protein
Tissue protein
drug
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Plasma Proteins

• albumin- primarily for acidic drugs
• a1-acid glycoprotein
• - for basic drugs
• Lipoproteins
• - for some drugs
• The fraction of total drug in plasma that is
  bound is determined by
• the drug concentration,
• its affinity for the binding sites, and
• the number of binding sites.

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Redistribution
Termination of drug action is normally by
biotransformation, but may also occur as a result
of redistribution between various compartments.
Particularly true for lipid-soluble drugs that
affect brain and heart.
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Redistribution
100
blood
Thiopental conc (as of initial dose)
brain
muscle
adipose
50
0
100
1
10
1000
minutes