- drug distribution- fev 2010
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Drug Distribution
UY/FMSB/L2S4
PHCL 2XX
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Definitions
Disposition: processes after drug administration that result in
decreasing drug concentration in blood
Distribution:
reversible transfer of drug to and from the site ofmeasurement (usually blood)
Elimination: irreversible loss of drug from the site of measurement
Excretion: loss of unchanged drug
Metabolism: conversion of drug to metabolite(s)
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The Compartment Model
WE can generally think of the body as aseries of interconnected compartmentswithin which the drug remains fairly
constant. Movement BETWEEN compartments
important in determining when and for
how long a drug will be present in body.
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Volumes of body fluids
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main compartments
plasma (5% of body mass)
intestinal fluid (16%)
intracellular fluid (35%)
transcellular fluid (2%)
fat (20%)
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Plasma 3.5 liters. (heparin, plasma expanders)
Extracellular fluid - 11 liters.(tubocurarine, charged polar compounds)
Intracellular water - 28 liters.
Total body water - 42 liters. (ethanol) Transcellular small. - CSF, eye, fetus (must
pass tight junctions)
Distribution into body
compartments
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Body Composition fromPharmacokinetic Viewpoint
fat-free tissues high water content, decreases with age mainly due to
reduction in extracellular water
lipophilic drug molecules bind to proteins and
accumulate in membranes body fat (adipose tissue)
practically no water
constant density ~900 g/L
lipophilic drug molecules
accumulate in membranes and in triglyceride oil that almostcompletely fills the adipocytes
bind to proteins
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Blood: Composition
plasma - rich in protein albumin (~5x10-4 mol/L)
1-glycoprotein (~1x10-5 mol/L)
lipoproteins (variable)
erythrocytes, ~ 5 millions/mm3
leukocytes, ~ 5 thousands/mm3 platelets, ~ 500 thousands/mm3
chylomicra (fat droplets)
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Factors Influencing Drug Distribution
pKa, lipid solubility, molecular weight
Blood flow to the tissue
Binding to macromolecules, such asplasma proteins and intracellular proteins
Anatomic barriers: Capillary endothelium,
BBB, etc.
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Transport of drug across Capillaries:
Morphology of cappilaries capillaries consist of
endothelial layer: large,polygonal, flat cells of irregular
shape, joined by interstitialcement substance
the basement membrane
diameter ~8 m and more
comparable to the diameter ofthe erythrocytes (pass slightlydeformed)
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Transport of drug across Capillaries-Porosity
The capillary walls in different organs are: Continuous capillary
continuous lining of epithelial cells uninterrupted layer of the basement membrane (brain and
central nervous system - blood brain barrier, intestine,muscles, connective tissues, loop of Henle, distal and
proximal tubule of the nephron, placenta, testis ) fenestrated
endothelial layer interrupted by fenestrae, which have 30 - 60nm in diameter
the basement membrane complete (renal glomerulus
Discontinuous endothelial layer has openings - 100-300 nm in diameter the basement membrane is missing (bone marrow, spleen,
tumors, sinusoids of liver)
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Transport of drug across Capillaries: -Permeability
fenestrated and discontinuous capillary walls very permeable, even to small peptides
no selectivity besides size limitations
continuous capillary walls
barrier function
selective permeability based on drug properties
active protein-mediated transport for intake of nutrients (glucose, amino acids, ions)
efflux of some substances (P-glycoprotein, MDRproteins)
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Tissue Uptake of drugs
tissue uptake (extravasation) drug molecules easily reach the interstitial
space through fenestrated and discontinuous
capillary walls transport through continuous capillary walls
and tissue cell membranes determined by therate of trans-bilayer transport (besides actively
transported drugs)
proceeds towards equilibrium of the drugbetween tissue and the blood perfusing it
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Tissue Uptake of drugs (contd)
the rate of tissue uptake can be perfusion limited (drug amount brought in the
bloodstream is completely distributed in the
1st run) permeability-limited (drug molecules stay in
the bloodstream for longer time)
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Drug Properties Determining Transport Rate andMembrane Accumulation
Lipophilicity
tendency to accumulate in the hydrophobic
core of the membranes parameter: the reference partition coefficient
Po/w
Amphiphilicity
tendency to adsorb to membrane/waterinterfaces
dramatically reduces the transport rates
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Partition Coefficient
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Blood Flow through Organs
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Drug Distribution and Protein Binding
protein binding is mostly fast and non-covalent
protein binding serves as depot for drugmolecules
protein binding attracts the molecules to thegiven compartment (the total concentration forthat compartment increases)
if it occurs in tissues, it increases VD
if it occurs in plasma, it decreases VD
protein-bound drug molecules are preventedfrom metabolism and excretion, but also cannot
elicit the effects
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Drug Binding Proteins
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Plasma Proteins that Bind Drugs
albumin: binds many acidic drugs and afew basic drugs
b-globulin and an 1acid glycoproteinhave also been found to bind certain basicdrugs
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A bound drug has no effect!
Amount bound depends on:1. free drug concentration
2. the protein concentration
3. affinity for binding sites
% bound: __[bound drug]__________ x100
[bound drug] + [free drug]
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Protein binding and drug interactions
Competition from other drugs can also affect %bound.
Example warfarin (anticoagulant) protein bound ~98%
Therefore, for a 5 mg dose, only 0.1 mg of drug isfree in the body to work! If pt takes normal dose of aspirin at same time
(normally occupies 50% of binding sites), the aspirindisplaces warfarin so that 96% of the warfarin dose is
protein-bound; thus, 0.2 mg warfarin free; thus,doubles the injested dose
Renal failure, inflammation, fasting, malnutritioncan have effect on plasma protein binding.
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Specific Tissue Distribution of drugs
Drugs may be stored in tissues differently.
Drugs are removed from circulation andstored in bone, teeth, hair and adipose
tissue. Lipid soluble drugs are stored in adipose
tissue, which increases during pregnancy,
with a resulting prolonged effect of thedrug (slow release).
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Tissue storage. Drugs may also accumulate in specific organs orget bound to specific tissue constituents, e.g.: Heart and skeletal muscles digoxin (to muscle proteins) Liver chloroquine, tetracyclines, digoxin Kidney digoxin, chloroquine Thyroid gland iodine Brain chlorpromazine, isoniazid, acetazolamide Retina chloroquine (to nucleoproteins) Iris ephedrine, atropine (to melanin) Bones and teeth tetracyclines, heavy metals (to mucopolysaccharide of connective tissue)
Adipose tissues thiopental, ether, minocycline, DDT
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Lymphatic System
Functions of lymphatic system: removal of excess interstitial fluid
transport of fatty acids from the GI tract to thebloodstream
production of immune cells (lymphocytes,monocytes)
the lymph components serve as drug carriers
albumin chylomicra (especially for lipophilic drugs)
cells
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Anatomic barriers
Feto-placenta barrier
BBB, etc.
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Drug Distribution in Fetus
capillary walls separating fetal blood frommaternal blood are continuous
many drugs can be found in fetus shortly after
the administration to mother fetus can be pharmaceutically treated through
mothers body
risk of the undesirable effects is high (testingof drugs for teratogenicity, minimal drug useduring pregnancy)
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The Placenta
Umbilical arteries
Umbilical vein
Chorionic villus
Placental septum
Endometrial
arteries
and veins
Intervillus space
Chorion
Amnion
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The Maternal-Fetal Unit
Maternal transfer Antibodies
Drugs
Hormones Nutrients
Oxygen
Pathogens
Vitamins
Viruses
Water
Fetal Transfer Urea
Carbon dioxide
Other catabolites
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CNS and CSFBlood-Brain Barrier (BBB) unique anatomical pattern of the vesselssupplying the brain
only highly lipid soluble compounds canmove across to the brain
infection of the meninges or brain:
higher permeability of penicillins to thebrain.
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Quantitative Study of DrugDistribution
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Drug distribution against time It takes time for a drug to distribute in the body
Drug distribution is affected by elimination
Time
Seru
mC
oncen
tration
0
0.5
1.0
1.5
0
Elimination Phase
Distribution Phase Drug is eliminated
Drug is not eliminated
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PK parameter for measurement of DrugDistribution
Apparent Volume of Distribution (Vd)
Vd influenced by body composition, proteinbinding and regional blood flow
In Neonates and infants
Increased Vd for water soluble drugs
Decreased Vd for lipid soluble drugs
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PK parameter for measurement of Drug Distribution:
Volume of distribution
Definition of Volume of distribution: Reflection of the amount left in the blood
stream after all the drug has been absorbed
if drug is held in the blood stream it will have asmall volume of distribution
if very little drug remains in blood steam has alarge volume of distribution
f f
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PK parameter for measurement of DrugDistribution
Apparent Volume of Distribution (Vd)
Vd influenced by body composition, proteinbinding and regional blood flow
In Neonates and infants
Increased Vd for water soluble drugs
Decreased Vd for lipid soluble drugs
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Volume of distribution- advanced
Formula for volume of distribution
V=D
C
V= volume of distribution
D= dose (assuming all a
absorbed)C= concentration in blood
stream
If you know the volume of distribution it is possible to calculate
the concentration in the blood stream for a particular dose
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Rapid (bolus) i.v. injection and uniform mixing of the
amount administered throughout the volume of total
body water:
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Calculation of Volume of distribution
Suppose there is a drug that gives aplasma concentration of 0.1mg/ml aftergiving a 1 gram bolus dose IV
V=1000mg/0.1 = 10 litres
Usually expressed as litres/kg body wt.
If this was a 50Kg person
V=0.2L/Kg
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How are [drug] measured?
Invasive:
blood, spinal fluid, biopsy
Noninvasive: urine, feces, breath, saliva
Most analytical methods designed forplasma analysis
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