Distribution - Lauver

⭐ 1. Q: What is drug distribution, and where does it occur in the ADME process?

Drug distribution is the reversible movement of drug from the blood/plasma into tissues and body fluids after absorption or injection.

🔎 What this means:

ADME describes what happens to a drug in the body:

• Administration

• Absorption

• Distribution

• Metabolism

• Excretion

After a drug enters the bloodstream, it can leave the blood and enter tissues and fluids. This movement is reversible, meaning drug can move between plasma and tissues rather than traveling only one way.

Early distribution is often mainly controlled by blood perfusion, or how much blood reaches a tissue. Later distribution is influenced more by whether the drug can cross tissue membranes.

💡 Think: Absorption gets the drug into the blood; distribution determines where it goes from there.

⭐ 2. Q: What are the major determinants of drug distribution?

The major determinants are:

• blood flow

• membrane permeability

• physicochemical properties

• plasma protein binding

• transporters.

🔎 What this means:

Once a drug is in the blood, several things determine whether and how quickly it reaches a particular tissue:

• Blood flow/perfusion: How much blood is being delivered to the tissue.

• Membrane permeability: How easily the drug can cross barriers between blood and tissue.

• Physicochemical properties: Features such as drug size, lipophilicity, charge, pKa, and logP.

• Plasma protein binding: Whether the drug is free or attached to proteins in the blood.

• Transporters: Proteins such as P-glycoprotein (P-gp), OAT, and OCT that influence drug movement at certain sites.

These factors help determine how quickly, how much, and where a drug distributes.

⭐ 3. Q: How does tissue perfusion affect the speed of drug distribution?

Drugs generally reach well-perfused tissues first and poorly perfused tissues later.

🔎 What this means:

Perfusion means blood flow through a tissue.

A drug cannot reach a tissue quickly if very little blood is being delivered there.

The lecture identifies these as highly perfused tissues that receive drug early:

• brain

• heart

• kidney

• liver

Poorly perfused tissues receive drug more slowly, including:

• fat

• skin

So early after a drug enters circulation, distribution is often perfusion-limited.

That means blood delivery is the main factor limiting how fast the drug gets there.

💡 Think: More blood arriving means more opportunities for drug to arrive.

⭐ 4. Q: How does membrane permeability affect drug distribution?

Distribution is greater when a drug can more easily cross tissue membranes, which depends on factors such as size, lipophilicity, charge, and the type of tissue barrier.

Some tissues contain larger paracellular gaps, allowing easier movement between cells.

Other tissues are much more restrictive. The blood-brain barrier (BBB) has tight junctions that greatly limit permeability.

This is why two tissues receiving similar blood flow may still receive different amounts of drug

⭐ 5. Q: How does plasma protein binding affect drug distribution?

Only unbound drug (fu) distributes across membranes and acts; therefore, high plasma protein binding decreases the free fraction of drug and tends to keep more drug in the plasma.

🔎 What this means:

Some drug molecules circulate attached to proteins in the blood. This is called plasma protein binding (PPB).

The lecture identifies:

• Albumin as an important binding protein for acidic drugs.

• α1-acid glycoprotein (AGP) as an important binding protein for basic drugs.

6. Q: What happens when another drug displaces a highly protein-bound drug from plasma proteins?

Protein displacement can temporarily increase the amount of free drug, but the effect is usually transient as distribution and clearance rebalance.

This matters especially for drugs with a narrow therapeutic index, where relatively small concentration changes can affect toxicity risk.

⭐ 7. Q: How can disease, inflammation, and species differences alter plasma protein binding and drug distribution?

Disease, inflammation, and species differences alter plasma protein binding and drug distribution because they can change levels of albumin or α1-acid glycoprotein (AGP), which changes how much drug is unbound and able to leave the plasma and enter tissues.

🔎 What this means:

• Albumin mainly binds acidic drugs.

  • Low albumin, such as with liver disease or cachexia (muscle wasting), means less acidic drug is bound.

  • This increases the free/unbound fraction, which can increase tissue distribution, drug effect, and Vd.

• AGP mainly binds basic drugs.

  • Inflammation and stress increase AGP.

  • More basic drug becomes bound, so the free/unbound fraction of basic drugs decreases.

• Species differences matter because AGP responses vary.

  • In cats, AGP can increase substantially during inflammation.

  • In ruminants, diet and stress can alter AGP levels.

These changes can affect drug effect, volume of distribution, and toxicity risk.

⭐ 8. Q: What is ion trapping, and what pH rule does this lecture want you to know?

Weak bases tend to become trapped in acidic environments, while weak acids tend to become trapped in more basic environments.

A clinically relevant example from the lecture is milk, which has a pH of approximately 6.5–6.8 and therefore favors trapping of weak bases.

⭐ 9. Q: How do the blood-brain barrier, placenta, privileged sites, and milk affect drug distribution?

These sites have distinctive permeability or pH properties that restrict or favor the distribution of particular drugs.

🔎 What this means:

Blood-brain barrier (BBB)

• Contains tight junctions and P-glycoprotein (P-gp).

• Favors small, lipophilic drugs that are not P-gp substrates.

• It is therefore much harder for many drugs to enter the brain.

Placenta

• Is not an absolute barrier.

• Lipophilic and unbound drugs can cross.

• P-gp provides some protection.

Eye, testis, and joints

• The lecture calls these “privileged sites.”

• They have restricted permeability.

• Inflammation increases drug penetration into these sites.

Milk

• Has a pH around 6.5–6.8.

• Favors weak-base ion trapping.

10. Q: What are the body-fluid compartments for interpreting volume of distribution?

The major reference volumes are approximately 0.04 L/kg for plasma, 0.2 L/kg for extracellular fluid, and 0.6 L/kg for total body water.

🔎 What this means:

The body contains several fluid compartments.

The lecture gives approximately:

• Total body water (TBW): 60% of body weight, about 0.6 L/kg

  • Intracellular fluid (ICF): 40% of body weight, about 0.4 L/kg

  • Extracellular fluid (ECF): 20% of body weight, about 0.2 L/kg

    • Plasma: about 4% of body weight, approximately 0.04 L/kg

    • Interstitial fluid: about 16%

These values are important because comparing a drug's Vd with these reference volumes gives you a clue about where the drug is distributed.

The lecture uses L/kg because normalizing volume to body weight allows comparison among animals of very different sizes.

⭐ 11. Q: What is volume of distribution (Vd), and why is it called an “apparent” volume?

Volume of distribution (Vd) is an apparent volume that relates the amount of drug in the body to its plasma concentration; it is not a real anatomical compartment.

🔎 What this means:

Vd is a way of describing how extensively a drug appears to have left the plasma and distributed throughout the body.

Vd = dose/concentration

After an IV dose, the initial plasma concentration, Cp₀, is often used.

The important idea is that Vd is a mathematical concept, not a literal fluid-filled space inside the animal.

A drug can even have a calculated Vd larger than the animal's actual body-water volume because the calculation reflects how little drug remains measurable in plasma compared with how much has moved into or bound within tissues.

⭐ 12. Q: How should you interpret a drug's volume of distribution?

A small Vd suggests the drug remains mainly in plasma or extracellular fluid, while a large Vd suggests extensive distribution or tissue binding.

🔎 What this means:

Use the body-fluid volumes as landmarks.

Very small Vd, around 0.04 L/kg

• Suggests the drug is largely confined to plasma.

Low Vd, around 0.1–0.3 L/kg

• Suggests the drug is mainly in plasma/extracellular fluid.

Vd around 0.6 L/kg

• Suggests distribution throughout total body water.

Vd greater than 0.6 L/kg

• Suggests substantial movement beyond body water and binding in deeper compartments such as adipose tissue or bone.

The next slide describes Vd >1 L/kg as suggesting extensive tissue binding.

💡 Think:

Small Vd = drug stayed near blood.
Large Vd = drug disappeared from plasma into tissues.

13. Q: How do edema, ascites, dehydration, and shock alter the volume of distribution of hydrophilic drugs?

Edema and ascites increase Vd, while dehydration and shock decrease Vd, and so hydrophilic drugs have less space to spread into (Vd decrease)

🔎 What this means:

Edema or ascites

• expand ECF

• provide more fluid space for a hydrophilic drug

• therefore increase its Vd

Dehydration or shock

• shrink the available fluid compartment

• therefore decrease Vd

The lecture also notes that hydrophilic drugs normally do not distribute beyond total body water, so Vd is generally ≤0.6 L/kg

⭐ 14. Q: How is volume of distribution used to determine a loading dose?

Loading dose is determined from the target plasma concentration multiplied by Vd, so a larger Vd requires a larger loading dose to reach the same target concentration.

🔎 What this means:

A loading dose is the amount of drug needed initially to achieve a desired plasma concentration.

The lecture gives:

Loading dose = target plasma conc. x Vd

So imagine two drugs need to reach the same target plasma concentration.

If Drug A has a much larger Vd, more of it distributes away from the plasma into tissues.

Therefore, you need a larger initial dose to reach the desired plasma concentration.

The lecture's wrap-up summarizes this relationship as:

Loading dose is proportional to Vd.

It contrasts this with maintenance dosing, which is related to clearance and is reserved for later material

⭐ 15. Q: A drug is given IV at 6 mg/kg, and the PK graph shows an initial plasma concentration (Cp₀) of 5 μg/mL. What is the Vd for a 50-kg dog?

PK = pharmacokinetic

First convert 5 ug/ml into 5 mg/L

Then 6 mg/kg ÷ 5 mg/L = Vd = 1.2 L/kg

50 kg dog x 1.2 L/kg = 60 L

this Vd suggests substantial tissue distribution/binding rather than confinement to plasma.

⭐ 16. Q: iClicker — Which statement about drug distribution is true?

A. High plasma protein binding always causes toxicity.
B. Plasma protein displacement effects are usually permanent.
C. Only unbound drug crosses membranes.
D. Tissue blood perfusion is not a major determinant of distribution.

C. Only unbound drug crosses membranes.

⭐ 17. Q: iClicker — A drug with a Vd of 0.2 L/kg is most likely located where?

A. Heavily tissue-bound
B. Mostly in extracellular fluid
C. Strong CNS penetration
D. Trapped in fat

B. Mostly in extracellular fluid.

🟡 LOWER PRIORITY 18. Q: What are the distribution phase, elimination phase, and redistribution after an IV bolus?

The early rapid decline in plasma drug can reflect distribution into tissues, while the later slower decline reflects elimination; redistribution can move drug from highly perfused organs into larger, slower tissues.

🔎 What this means:

After an IV bolus, plasma concentration may fall rapidly even though the drug has not yet been eliminated from the body.

The lecture describes:

Early α phase: distribution

• drug rapidly leaves the blood

• drug enters well-perfused organs such as the brain and heart

Later β phase: elimination

• after near-equilibrium, the slower decline reflects actual removal of drug from the body

Redistribution

Drug can later move from:

• high-perfusion, low-capacity tissues such as brain and heart

into:

• larger, slower tissues such as muscle and fat

This can make the drug's effect disappear even though the drug is still present somewhere in the body.

The example given is thiopental: it rapidly enters the brain, then redistributes into muscle and fat, producing a short CNS effect despite longer body presence