Distribution

What is distribution

The movement of a xenobiotic from the systemic circulation into different tissues and organs

What are different locations where a xenobiotic is distributed theoretically called

Compartments

What is the “central compartment”

the systemic circulation

What are “peripheral compartments”

organs and tissues such as liver, brain, and other tissues

After absorption into systemic circulation, where does xenobiotic distribute most rapidly

Well-perfused tissues

What are the four main factors influencing distribution

1. blood flow

2. physicochemical properties

3. binding to plasma/cellular proteins

4. barriers to distribution

Why is blood flow important for distribution

xenobiotics are delivered to tissues through blood

What physicochemical properties affect distribution

• lipid solubility

• pKa

• molecular size

What is the most abundant plasma protein involved in xenobiotic binding

Albumin

Is binding between xenobiotics and plasma proteins permanent

No, it’s reversible, creating a free: bound equilibrium

What are the two forms of a xenobiotics and plasma proteins

free and protein-bound

which form can diffuse out of the bloodstream into tissues

Free xenobiotic

Why can’t protein-bound xenobiotics easily leave the bloodstream

plasma proteins are very large and can’t cross capillary walls

What happens when free xenobiotic leaves the blood and enters tissues

More xenobiotic is released from plasma proteins to maintain the free:bound equilibrium

What happens when free xenobiotic is excreted

More xenobiotic is released from plasma proteins

Why is plasma protein binding considered dynamic

because xenobiotic continually shifts between free and bound forms

Which organs have high binding capacity for certain xenobiotics

liver and kidney

what type of xenobiotics are particularly likely to accumulate in fat?

Highly lipophilic persistent organic pollutants (POPs)

What makes the BBB an effective barrier

• tightly joined endothelial cells

• Active ATP-dependent transporters that remove xenobiotics

What is volume of distribution

The apparent fluid volume in which xenobiotic appears to be dissolved; it indicated how widely a xenobiotic is distributed throughout the body

What is VD used for

To compare the distribution of xenobiotics, particularly pharmaceuticals

What does a high VD indicate

Extensive distribution of the xenobiotic and high affinity for tissues

What does a low VD indicate

the xenobiotic is mainly restricted to blood plasma, often due to high plasma protein binding