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Distribution of Drugs
Prepared by: Mr. Jitendra L Patel
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Introduction
Disposition
w Distribution
w Elimination
Biotransformation
Excretion
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Steps in drug distribution
w Permeation of free drug through capillary
wall & entry in to ECF.
w
Permeation of drugs from ECF to ICFthrough membrane of tissue
cell.
Rate limiting steps
Rate of perfusion to the ECF
Membrane permeability of the drug
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Factors affecting distribution of drugs
1. Tissue permeability of drugs
2. Organ tissue size and perfusion rate
3. Binding of drug to tissue component.
4. Miscellaneous
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1. Tissue permeability of drugs
1. Physicochemical properties of the drug
molecular size,
pKa and
o/w partition co efficient.
2. Physiological barrier to diffusion
Simple capillary endothelial barrier
Simple cell membrane barrier
Blood Brain Barrier BloodCSF barrier
Blood placental barrier
blood testis barrier
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1. Tissue permeability of drugs1. Physicochemical properties of
the drug
Molecular size: salicylic acid
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1. Tissue permeability of drugs1. Physiological barrier to the
diffusion:
Simple capillary endothelial barrier: drugs withmolecular size
< 600 d easily diffuse.
The simple cell membrane barrier : it is similar to
the lipoidal barrier in the GI absorption of the
drugs.
B.B.B: highly specialized and less permeable to
water soluble drugs.
Brain capillary consist ofendothelial cells whichare joined
another bycontinuous tight intercellular
junctions.
Pericytes & astrocytes form a solid envelop around
brain capillary & block intercellular passage.
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1. Tissue permeability of drugs1. Physiological barrier to the
diffusion:
A solute may enter to brain via:1. Passive diffusion through the
lipoidal barrier
2. Active transport of essential nutrients
BBB crossing can be promoted by:
1. Use of permeation enhancer like DMSO.2. Osmotic disruption of
the BBB by infusing
internal carotid artery with Mannitol
3. Use of dihydropyridine redox system as a drug
carriers
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1. Tissue permeability of drugs1. Physiological barrier to the
diffusion:
Blood cerebrospinal fluid barrier: formed by thechoroid plexus
of the lateral, third & fourth
ventricles .
It is similar to ECF of brain.
The capillary endothelium that line choroid plexus
have open junctions or gaps and drugs can flow
freely.
The choroid cells are joined to each other by tightjunctions
forming the bloodCSF barrier which
has permeability characteristic similar to BBB.
For any given drug, its conc in brain > in the CSF.
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1. Tissue permeability of drugs1. Physiological barrier to the
diffusion:
Blood placental barrier:. The maternal & foetalblood vessels
are separated by a number oftissue
layers made of foetal trophoblast basement
membrane &endothelium which together
constitute the placental barrier.
Thickness :25 um in early pregnancy that reduce
to 2um at full term.
Drugs having molecular size less than 1000 d andmoderate lipid
solubility cross the placental
barrier.
E.g. ethanol, sulphonamide, barbiturate, Narcotic
analgesic, anticonvulsant etc.
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1. Tissue permeability of drugs1. Physiological barrier to the
diffusion:
Blood testis barrier:. Located not at the capillaryendothelium
level but at the sertoli-sertoli cell
junction.
It is tight junction between neighboring sertoli
cells that act as barrier.
It restrict the passage of drugs to spermatocyte and
spermatids.
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Organ/Tissue size & perfusion rate
w Distribution is permeability related in
following cases When the drug is ionic/polar/water soluble
Where the highly selective physiology
barrier restrict the diffusion of such drugs tothe inside
diffusion of such drugs to the
inside of cell.
w Distribution bill be perfusion rate limitedWhen the drug is
highly lipohilic
When the membrane is highly permeable.
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Organ/Tissue size & perfusion rate
w Perfusion rate : it is defined as the volume of
the blood that flows per unit time per unitvolume of the
tissue.
w Unit: ml/min/ml
w Kt = perfusion rate / Kt/b
w Distribution half life = 0.693/Kt
w = 0.693 Kt/b/perfusion rate
w
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Organ/Tissue size & perfusion rate
w Perfusion rate : it is defined as the volume of
the blood that flows per unit time per unitvolume of the
tissue.
w Unit: ml/min/ml
w Kt = perfusion rate / Kt/b
w Distribution half life = 0.693/Kt
w = 0.693 Kt/b/perfusion rate
w
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Binding of drug to tissue
components
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