BIOC 3310 - Drug Distribution

Drug Distribution refers to

the movement of a drug from the bloodstream into various tissues of the body

refers to the movement of a drug from the bloodstream into various tissues of the body (for example, fat, muscle, and brain tissue) and into

the site of target cells/tissues.

Drug distribution is the combination of

1.Perfusion

2. Permeability

1.Perfusion

"An organ with high blood perfusion will have more

exposure to the drug."

Permeability

"An organ whose capillaries' membranes are restricted will have less

concentration of the drug than the organ with high membrane permeability capillaries

Within the bloodstream, there are...

•Commonly mentioned proteins:

-Albumins (60%, create oncotic pressure and transports other molecules),

-Immunoglobulins (18%, immune system) and

-Fibrinogens (4%, blood coagulation)

•Total serum protein in blood is 7g/dl (7g/100mL), including

ØCirculatory transport molecules for lipids, hormones, vitamins and metals

ØEnzymes, complement components, protease inhibitors, and kinin precursors

ØProteins involved in the regulation of cellular activity and functioning and in the immune system

Interactions of drugs with plasma proteins are

low affinity, high capacity

Drugs may be bound to plasma proteins such as albumin

Only free (unbound) drug can cross

membranes, bind to receptors and be excreted by the kidney

Taken perfusion and permeability together, the rate and extent of drug distribution are influenced by

Rate of distribution and Extent of distribution

Terminology: these terms are used when an action of a drug is delayed due to

drug distribution to different tissues

•When the drugs' action(s) are delayed or ineffective due to the nature in the distribution, we identify the drugs as:

Drugs with perfusion-limited actions and Drugs with permeability-limited actions

Drugs with perfusion-limited actions

Used in describing the lack or slowness of the drug action due to the

target organs have low perfusion rate

Drugs with permeability-limited actions

Used in describing the lack or slowness of the drug action due to the

•drug ability to move across biological membrane to target organs/sites

Body Fluid « Rule of 60 : 40 : 20 »

60% of body weightisfluid/water, of which 40% is in

intracellular and 20% in extracellular.

Out of 20% fluid, 5% is blood,

15% found between cells

Body Fluid « Rule of

60 : 40 : 20

Pattern 1: Drugs with a high affinity to plasma protein and

remain in the plasma

Pattern 2: Distribute uniformly throughout the

body

Small molecules with similar structures to small natural metabolites

Ex. D2O, alcohol, sulfonilamide, antipyrine

Pattern 3: Drugs with specific properties that allow them to

concentrate or accumulate at a particular tissue or organ

Pattern 4: Combination of

•patterns

•Most drugs' distribution pattern

•Non-uniformly distribute dues to body's compartments (macromolecules binding), drug properties

Pattern 1= Found when drugs that are

high MW and highly charges remain in the blood vessels following injection

Pattern 2 = when the drugs are

•low MW, able to follow the distribution of water molecules to enter and leave the cells and interstitial fluid

Pattern 3 = when the drugs have

specific affinity towards organ- or tissue-specific molecules

Pattern 4 = Most drugs show this pattern of distribution (found in

the blood and different tissues)

In pharmacology we use the term "apparent volume of distribution (Vd)" to describe the properties of the

drug and how well the drug distribution is

•Not a real volume

•A hypothetical volume of fluid into which the drug distributes

Volume of the

virtual pool of liquid required to account for the observed drug concentration in the body

Unit of Vd is

L/kg

Where and how do we know the pattern of drug distribution and Vd?

Experiments during a

•preclinical trial

•Biochemical studies of the drug properties (ability to enter and be retained in a tissue and to bind (interaction) to protein in the compartment

•clinical trial

•Blood and tissue sampling

•For determination of loading dose (how much an initial dose) to give to a patient to give a desired plasma drug concentration (Cp)

Loading dose =

Vd * target Cp

Ex. calculate the loading dose of theophylline at the start of an IV infusion if Vd = 0.5 L/kg and the desired Cp = 10 mg/L.

Loading dose will be 0.5 L/kg * 10 mg/L

= 5 mg/kg

If a person weighs 70 kg, we need to give 350 mg to that person.