Distribution

Bahaa El Merhabi
 Definition
Distribution is the mechanism by which a drug is distributed to organs and tissues. It’s
mainly done through the circulatory system.
Considering the drug to be a lipid soluble drug so it can
Mechanism of distribution:
bind to plasma proteins.

Bound to tissue proteins..

free Highly vascularized tissues

Initial amount of
⇔ ( brain, kidneys, liver…)
Free
drug at time 0
Bound to plasma
 

proteins

free

Poorly vascularized tissues

( fat, muscles ….)
bound
 So first, the drug must be fractioned between bound and free forms in plasma.
What determine the fraction of drug that will bind to plasma proteins is:
1- concentration of drug
2- affinity of the drug to binding site
3- number of available binding sites which is saturable

Then the remaining free amount will be distributed to tissues.

Capacity of a tissue to uptake the drug depend on:

Rate of delivery and the amount of drug arriving to this specific The capacity of the tissue to sequester the drug,
tissue, it depends on: it depends on:
1- Blood flow of this tissue ( determined by CO and vascularization)
2- Capillary permeability ( fenestrated in liver & spleen & pancreas and tissue binding proteins and molecules
continuous in brain drugs must pass through the endothelial cells of
the CNS capillaries or undergo active transport)
3- Free form drug in the plasma
4- Drug characteristic (weak acid or base (ionized or not at
physiological pH) , more lipophilic  dissolve in the cell membrane
and pass easily)
Apparent volume of distribution
  the theoretical volume that would be necessary to contain all the initial dose at the same conc. that is in
It’s
the plasma.
Quantitatively :

Vd reflects the amount of drug distributed to the extravascular tissues: more Vd is high (C0 is
low) , the more the drug is distributed to the tissues.

Factors affecting Vd:

1- High drug-Plasma proteins  low Vd
2- High drug- tissue binding proteins  high Vd
3- High lipid solubility of the drug and low ionized form  high Vd

Vd is a useful pharmacokinetic parameter for calculating the loading dose of a drug.

Any factor that increases Vd will increase the half life
Any Vd > 42 L is considered high
NB. Some drugs have Vd in hundreds and thousands
 Reversible binding to plasma proteins sequesters drugs in a non
Plasma binding proteins diffusible form and slows transfer out of the vascular compartment
(tissues or being excreted in elimination organs)
albumin for acidic drugs , it’s the major Bin. Prot. and may act as drugs reservoir ( not selective)
alfa-acid-glycoproteins for basic drug
specific hormone carrier proteins as sex-hormone-binding protein and thyroxin binding protein
non specific binding which is very low
This process is saturable and reversible. when [free-drug] decreases  dissociation from binding proteins so the plasma conc.
is constant
1- decrease diffusion and transport to tissues
2- decrease renal excretion( transport and metabolism in general) bcz
Any factor than increases binding only free form can be filtrated in glomeruli
of drug to plasma proteins will : 3- increase the dose needed for therapeutic effect
e.g. the acute phase reaction response (e.g. cancer, arthritis, myocardial
infarction, and Crohn’s disease) increases alfa-acid-glycoproteins 
increase binding of basic drugs.
1- increase diffusion and transport to tissues
2- increase renal excretion
Any factor that decreases binding 3- decrease the dose needed for therapeutic effect
to plasma proteins will e.g. hypoalbuminemia  increase free form of acidic drugs
e.g. competition of 2 drugs on the same site of binding ( displacement of
unconjugated bilirubin by sulfonamide and other anions from its binding
site on albumin  neonatal bilirubin encephalopathy)
Fat as reservoir:
- Reservoir for highly lipid soluble drugs
- Stable reservoir because low blood supply
- E.g. highly lipid soluble barbiturate (thiopental) , as much as 70% of it stays in the fats after 3h of its
administration

Bone as reservoir
- Tetracycline antibiotics and heavy metals accumulate by adsorption onto the bone cristals
and eventual incorporation in the crystal lattice
- Bone will then act as a reservoir for slow release of toxic agents such as lead
- anti osteoporotic treatment : Phosphonates such as sodium etidronate bind tightly to
hydroxyapatite crystals in mineralized bone matrix. (ont un effet antiostéoclastique,
réduisant la resorption osseuse et entrainant un gain progressif de la masse osseuse)