Phar 204 - Distribution

What is distribution

the movement of a drug from the bloodstream to tissues / site of action

Distribution is reversible / irreversible

reversible

• drugs can re-enter the bloodstream for redistribution

What influences how drug is distributed throughout the body?

• properties of the drug

• characteristics of the body

Explain the mathematical model in the context of distribution

the body is divided into hypothetical compartments that connect to simplify how drugs move between them. This makes understanding drug distribution easier.

Blood is a complex mixture containing dissolved substances;

salt

glucose

drugs

plasma

cells

Plasma

the liquid part of the blood responsible for carrying everything including dissolved substances and blood proteins

Plasma contains water and plasma proteins, what are some examples of plasma proteins?

albumin 60%

globulin 30%

fibrinogen and prothrombin 4%

Red blood cells remain in blood vessels are are responsible for transporting…

O2 and CO2 bound to Hb

Can white blood cells enter and exit the bloodstream?

Yes

TRUE or FALSE
Platelets lack a nucleus

TRUE

they are cell fragments lacking a nucleus

What do drugs do when they are absorbed into the bloodstream?

• bind to plasma proteins → can’t leave the bloodstream

• unbound and uncharged → leave the bloodstream

• unbound and ionized →leave the bloodstream

Plasma proteins bind drugs ….. (specifically / non-specifically)

non-specifically

The binding of plasma proteins to drugs is …. (reversible / irreversible)

reversible

unbound and uncharged drug molecules can leave the blood stream through

paracellular transport (squeeze between endothelial cells) or diffusion (through the cell)

unbound and ionized drug molecules can leave the bloodstream by

paracellular transport (only if small enough) and active transport (because ionized)

Drugs in plasma is a mixture of

bound drug and free drug

What is the major drug-binding protein and is synthesized in the liver

albumin

albumin has how many drug binding sites?

two main drug binding sites

Albumin has a high ability to bind a wide range of molecules with

high affinity

Albumin primarily binds to what type of drugs

acidic ( neg. charge / donate proton)

neutral

What proteins in plasma has concentration changes in response to inflammation, infection and injury?

alpha - 1 - acid glycoprotein

Alpha-1-acid glycoprotein binds a small range of molecules with a

high affinity

Alpha-1-acid glycoprotein primarily binds to what type of drugs

basic (pos. charge / accept proton)

neutral

Distribution is driven by a

dynamic equilibrium between bound and free drug

Explain the dynamic equilibrium in distribution

as free drug leaves vascular space, the equilibrium will readjust to replenish the free drug

A drug is known to be 98% albumin bound. Which patient most likely has higher free drug at the same total concentration?

A patient with low albumin levels

Once a drug leaves the bloodstream, it distributes into the

interstitial fluid until equilibrium is reached

meaning that the drug concentration in the interstitial fluid will be equal to the free drug concentration in plasma

What is the effect of active transport on the equilibrium when free drug continues to distribute from the interstitial fluid into the cells of the tissue

it could lead to higher drug concentrations in cells than outside of the cells (goes against the equilibrium)

What is V_d (Volume of Distribution)

drug’s propensity to either stay in the plasma or distribute to tissues

Drugs that have high Vd will

leave the bloodstream and go into tissues

Drugs that have a low Vd will

stay in the bloodstream

Formula of Vd

Most drugs distribute by passive processes, but polar and ionized drugs depend on….to enter tissues

Uptake transporters → Solute Carrier (SLC) family proteins (facilitative transporters/active transporters)

What is redistribution

drugs move back from tissues to blood as drug plasma levels fall

Redistribution occurs primarily through what types of transport?

paracellular transport

passive transport

(across the endothelium)

As drugs leave the bloodstream and then are metabolized/excreted, the drug plasma concentration becomes ….. than the drug tissue concentration, so they have to distribute to the opposite direction

lower

Redistribution is important for eventual ….

removal of waste

Only what type of drug (free/bound) can redistribute back into bloodstream

free

Explain the whole process of distribution (bloodstream → endothelium → ISF → epithelial and tissue cells → tissue → epithelial and tissue cells → tissue → ISF → endothelium → bloodstream)

• in bloodstream, drug binds and unbinds proteins until equilbrium is reached

• free drug leaves bloodstream, pass through endothelium into ISF until equilibrium is reached

• free drug pass from ISF through epithelia and tissue cells until equilbrium is reached

• free drug leave tissues by passing through epithelia and tissue cells into ISF until equilibrium is reached

• free drug re-enters blood stream when passing from ISF through endothelium until equilbrium is reached

A drug is 99% plasma protein-bound. Which statement best predicts its initial distribution into tissues?

it will distribute more slowly because only free drug can leave plasma

To be distributed, drugs need to be somewhat soluble in polar and non-polar environments, meaning that they need to have…

both hydrophilic and lipophilic properties

Why does a drug need to have some hydrophilic properties

to move through aqueous blood, ISF and intercellular fluid

Why does a drug need to have some lipophilic properties?

to cross the cell membranes

Lipophilic (hydrophobic) drugs are more likely to pass through lipid bilayer so they are more likely to

leave the bloodstream and distribute to tissues, so they have a higher Vd

• lipophillic →higher Vd

Polar drugs are less likely to pass through lipid bilayers and therefore more likely to

stay in the bloodstream, so they have a lower Vd

• hydrophilic → lower Vd

simvastatin

As the drug becomes more lipophillic, what’s the effect on protein binding in plasma

it increases protein binding in plasma (driven by hydrophobic interactions), the more bound they are, the less distribution

How can a lipophilic drug both have increased distribution due to being able to easily cross cell membranes and have decreased distribution due to increased plasma protein binding?

• it’s complicated

• drugs that are highly bound to plasma proteins have a longer duration of action but may also exhibit reduced volumes of distribution

Compare the distribution of big vs small drugs

small drugs are more likely to pass through endothelium, leave bloodstream, and distribute to tissues thus a higher Vd

big drugs are less likely to pass through endothelium, leave bloodstream, and distribute to tissues thus a lower Vd

Physiological properties that impact drug distribution are

• blood flow and perfusion

• protein binding

• tissue type

• biological barriers

What is perfusion?

Perfusion is the extent to which your body’s tissue and organs are supplied with blood vessels

Highly perfused tissues have a large amount of

vasculature, therefore a high amount of blood flow to the area

• brain, heart, liver, kidneys, lungs

lower perfused tissues have very little

vasculature, therefore have a small amount of blood flow to the area

• muscle, skin, fat, bone

Compare tissues with high and low perfusion in the context of receiving drugs

High perfusion → high blood flow → receive drugs more quickly

Low perfusion → low blood flow → receive drugs slowly

A patient is in shock and experiences strong vasoconstriction. Compared to a healthy patient, which tissue is most likely to receive even less early drug exposure?

A. Brain

B. Heart

C. Kidney

D. Skin

Skin

Is protein-bound drug pharmacologically active?

No. Bound drug is inactive

What is meant by a “circulating drug reservoir”?

Protein-bound drug remains in plasma and serves as a reserve

What happens as free drug is eliminated from the body? (causing depleting tissue and isf concentrations)

protein-bound drugs in plasma will dissociate to maintain plasma levels

this creates a plasma reservoir that buffers free drugs

What is the buffering effect of plasma protein binding

it creates a plasma reservoir that buffers free drug concentrationn

How does plasma protein binding affect volume of distribution (Vd)?

It doesn’t necessarily increase VD and often lowers apparent Vd

What is the overall clinical effect of plasma protein binding on drug action

prolonged duration of action

A drug is predicted to be 90% bound in a healthy individual. What potential impact(s) could occur for an individual with severely impaired liver activity who takes the same dose of the same drug

• reduced albumin production could increase free fraction of the drug

• free drug concentration could rise more than expected, increasing risk of toxicity

Can drugs bind to tissue components? If yes, what does that mean

Yes

it means that there is less free drug available to move through the body and interact with their targets

(some drugs have a strong affinity for a tissue component, depleting it from the bloodstream)

drugs can bind to tissue proteins and other macromolecules through

non-specific or specific interactions

As free drug concentrations decrease in the ISF, tissue-bound drug will be…

released to restore equilibrium

There are two types of tissue reservoirs;

fats reservoirs and bone reservoirs

Explain fats reservoir

lipophilic drugs are bound to fat tissue and get trapped, since fat as low blood flow, the drug uptake and release is slow (released slowly back to circulation), so there is a prolonged duration of action

(e.g cannabis)

Explain bone reservoirs

some drugs have high affinity for calcium crystals in bone mineral, and bind tightly to bone through ionic interactions

(e.g biphosphonates)

A patient with high body fat receives a lipophilic drug. Predict how the distribution of drug would compare to a patient with less body fat

More drug is trapped in fat, and less is in the bloodstream, so there is a higher Vd

• it will have a higher Vd

Biological barriers act as a semipermeable membranes to

block interaction of foreign materials with cells beyond the barrier

Barriers limit the molecules that can pass through, forming / producing…

• tight cell-cell junctions

• efflux transporter proteins

The existence of biological barriers mean that

a drug may not be able to be distributed to certain areas of the body

Brain endothelium is very tightly packed, why?

to restrict any entry to the brain through paracellular transport

What additional barrier of cells wrap around the brain’s capillaries, and what does it do?

astrocytes

prevent influx of materials

What do efflux transporters at the BBB to

pump out foreign materials that manage to sneak in

BBB prevents distribution of many drugs to the brain

How do drugs distribute into the brain?

By satisfying the Lipinski rule of 5

What is the Lipinski rule of 5?

• < 500 g/mol

• log P < 5

• < 5 H-bond donors

• < 10 H-bond acceptors

• uncharged at physiological pH

• Example drugs: pain relievers, antidepressants, nicotine

Many drugs can still distribute into the brain through the BBB, how though?

active and receptor-mediated transport through binding to receptors on the brain’s epithelial cells

In order to get drugs through the BBB, we have to design drugs that

mimic the natural substrates for specific receptor proteins at the BBB

e.g: semaglutide

Another example of how drugs can still distribute into the brain through the BBB is through Adsorptive-mediated transport, what does that mean

the drug has a lipid nanoparticle-encapsulated drug adsorb to plasma membranes to support passage through cells

Explain the internasal route of administration

internasal delivery can allow some drugs to travel into the brain through olfactory nerves

e.g: naloxone

A drug meets Lipinsi’s Rule of 5 but still has low accumulation in brain tissue. What is the most likely reason?

the presence of efflux transporters pump the drug out of the brain

What is the Blood-Testes barrier (BTB)

barrier that separates developing sperm cells from the bloodstream

BTB is formed by

tight junctions between sertoli cells that prevent paracellular transport

Some drugs can make it through the BTB if they

• satisfy Lipinski’s Rule of 5

• transported via active transport mechanism

Does the BTB also have efflux transporters

Yes, their efflux transporters work to pump out the drugs

What does the Placenta Barrier do?

separates maternal and fetal circulation

What creates a large surface area for nutrient and waste exchange?

stem cells called cytotrophoblasts that fuse to make a synctiotrophoblast

Does the placenta barrier have a tight regulation like BBB?

No, it’s more lax

What type of drugs can easily diffuse through the placenta

small lipophilic drugs

• drugs that are very large, ionized or have strong protein binding are less likely to pass through the placenta

So many physiological factors impact distribution, like

• age

• pregnancy

• obesity

• various disease states

• diet

• drug interactions

(see slide 49 of distribution lecture for more detail)