- drug distribution- fev 2010

7/29/2019 - 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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- drug distribution- fev 2010

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