DRUG DISTRIBUTION

DISTRIBUTION

—Drug distribution refers to the movement of drug to and from the blood and various tissues of the body (for example, fat, muscle, and brain tissue) and the relative proportions of drug in the tissues.

—After a drug is absorbed into the bloodstream, it rapidly circulates through the body. The average circulation time of blood is 1 minute. As the blood recirculates, the drug moves from the bloodstream into the body's tissues.

Determinant of Drug Distribution

 

DISTRIBUTION SPACE

The drug molecules are carried by the blood to :

Circulatory system consists of a series of blood vessels:

• Arteries: carry blood to tissues

• Veins: return the blood back to the heart

Drugs molecules rapidly diffuse through a network of fine capillaries to the tissue spaces filled with interstitial fluid, further may diffuse from interstitial fluid across the cell membrane into the cell cytoplasm.

The passage of drug molecules across
a cell membrane depend on: 

 
Physicochemical Nature of group of drug related to Drug Distribution

 

 

Drugs which have VD of 12 L : distributed in extracellular fluid but not penetrated the cell

Drugs which have VD of 3 L (the plasma protein

    binding are high, MW are high) : distributed only in vascular compartment

Diffusion and Hydrostatic Pressure

The processes involved in capillary membrane transverses

• Passive diffusion : Fick’s law

  dQ/dt = - DKA (Cp-Ct) / h

• The negative sign means net transfer of drug from inside the capillary lumen into the tissue and extracellular sources

• Diffusion is spontaneous and temperature dependent

  Hydrostatic pressure = pressure gradient between the arterial end of the capillaries entering the tissue and the venous capillaries leaving the tissue and responsible for penetration of water soluble drugs into spaces between endothelial cells and possibly into lymph

• In the kidney high arterial pressure creates a filtration pressure that allows small drug molecules to be filtered in the glomerulus of the renal nephron

Distribution of drug entering the cell
with blood-flow induced mechanism

• Blood-flow induced drug distribution is rapid and efficient, but requires pressure

• Blood pressure (BP) decreases when arteries branch intosmall

  arterioles      flow speed lows  diffusion into interstitial fluid depends on gradient concentration and facilitated by the large surface area of the capillary network

• The average pressure of the blood capillary (18 mm Hg) is > mean tissue pressure (-6mm Hg), net total pressure=24 mmHg higher in the capillary over the tissue

• This pressure is offset by osmotic pressure=24 mm Hg, pulling the plasma fluid back into the capillary

• On average, pressure in tissue = pressure in capillary » no net flow of water

• At the arterial end, the blood enters the capillary, the pressure at the capillary slightly > than tissue           fluid leave the capillary into the tissue   hydrostatic or filtration pressure

• The filtrate water later returned to the venous capillary due to lower venous pressure than tissue called absorptive pressure

• A small amount of fluid return to the circulation through the lymphatic system

Permeability of Cell and Capillary Membranes

• Cell membrane vary in their permeability characteristics, depending on the tissue.

• Liver and kidney: more permeable to transmembrane movement than capillaries in the brain. The sinusoidal capillaries of the liver are very permeable and allow the passage of large-molecular-weight molecules.

• In the brain and spinal cord, the capillary endothelial cells are surrounded by a layer of glial cells, which have tight intercellular junctions, acts effectively to slow the rate of drug diffusion into the brain by acting as a thicker lipid barrier.

• This lipid barrier, which slows the diffusion and penetration of water soluble and polar drugs into the brain and spinal cord, is called the blood brain barrier.

•  The diameters of the capillaries are very small and the capillary membranes are very thin. The high blood flow within a capillary allows for intimate contact of the drug molecules with the cell membrane, providing for rapid drug diffusion.

•  For capillaries that perfuse the brain and spinal cord, the layer of glial cells functions effectively to increase the thickness of term h in Fick’s equation, there by slowing the diffusion and penetration of water soluble and polar drugs into the brain and spinal cord.

•  In disease, the permeability of cell membranes, including capillary cell membranes, may be altered by burns (on the skin-large molecules can permeate inward or outward), inflammation (meningitis) – drug uptake into the brain will be enhanced.

Distribution half-life, Blood flow, Drug uptake by Organ

• Drug transfer from the capillary into the tissue fluid is mainly diffusion process : h, D, (Cp-Ct) are important factors in determining the rate of drug diffusion. If drug distribution is limited by the slow diffusion, the process is diffusion / permeability limited

• If drugs diffuse rapidly across the membrane that blood flow is a rate limiting step in the distribution of drug, the process is perfusion / flow limited. Congestive heart failure -reduced filtration pressure and blood flow.

Drug Accumulation

• The deposition or uptake of the drug into the tissue is controlled by the diffusional barrier of the capillary membrane and other cell membrane

• The brain is well perfused with blood, but many drugs with good aqueous solubility which have high kidney, liver and lung concentrations, yet little brain drug concentration.

• The brain capillaries are surrounded by a layer of tightly joined glial cells that act as a lipid barrier to impede the

  diffusion of polar or highly ionized drugs.

• A diffusion limited model may be necessary to describe the pharmacokinetics of these drugs that are not adequately described by perfusion models

• The accumulation of drug into tissues is dependent on:

  - the blood flow

  - the affinity of the drug for the tissue

• Drug uptake into a tissue is generally reversible

• The drug concentration in a tissue with low capacity equilibrates rapidly with the plasma drug concentration and then declines rapidly as the drug is eliminated

• Drugs with high tissue affinity tend to accumulate or concentrate in the tissue

• Drugs with a high lipid /water coefficient partition are very fat soluble and tend to accumulate in lipid or adipose tissue

Apparent Volume of Distribution

•  The concentration of drug in plasma or tissues depends on the amount of drug systematically absorbed and volume in which the drug is distributed

•  Apparent volume of distribution, VD = the volume in which the

  extent of drug distributed in the body, represents the result of dynamic drug distribution between the plasma and the tissues and accounts for the mass balance of the drug in the body

•  The volume of the system may be estimated if the amount of drug added to the system and the drug concentration after equilibrium in the system are known

•  Volume of distribution, ( VD , L) = amount (mg) of drug in body/drug concentration (C, mg/L) in plasma after equilibrium

Apparent Volume of Distribution, Vapp

• Vapp is different from VDss (compartment model)

• Vapp = DB / CP

• DB = VPCP + VtCt

• DB = amount of drug in the body;  VP = plasma fluid volume; Vt = tissue volume;  CP = plasma drug concentration; Ct = tissue drug concentration

• For many protein bound drugs, the ratio DB/CP is not constant every time, depends on the nature of dissociation of the protein-drug complex and how the drug is distributed; the ratio is best determined at steady state.

• Protein binding to tissue – apparent volume of distribution increase. Some models: the drug distributes from the plasma water into extracellular tissue fluid, where the drug binds to extravascular proteins, resulting in a larger VD due to extracellular protein binding

Protein binding in drug distribution 

Plasma Protein Binding

—Proteins involved

—Albumin

—glycoprotein

—lipoprotein

—Globulins
 

Drug bind with Plasma Protein :

—a big complex

—Can’t through cell membranes

—Limited distribution

—Not active therapeutic
 

Free Drug :

—Free through cell membranes

—Large Distribution

—Active Therapeutic 

Plasma Protein Binding Depends of :

—Physicochemical nature of drug

—Drug concentration in blood

—Amount of plasma protein

—Affinity drug with protein

—Competition drug with another on protein binding

—Patients pathology condition

Tissue Protein Binding

—Binding to intracellular molecules, drug receptor >> pharmacological effect

—Binding to tissue protein (albumin, etc.), nucleic acids, or dissolution in lipid

  – e.g. chloroquine in liver > DNA

  – barbiturates > adipose tissue

  – tetracycline > bone

—Difficult to measure - disrupt binding

   

Protein Binding Interaction

—One drug may displace another from the same binding site

—One drug bound may alter binding of another

—Interactions can occur when one drug displaces another

—Free drug concentration usually the important factor with drug activity

—Higher free drug concentration often causes an increase in elimination