PHC5005 Chap.2 Drug Distribution and Volume of Distribution
Drug Distribution and Volume of Distribution
From the bloodstream to the tissues
Distribution is the second pharmacokinetic process: the reversible movement of an absorbed drug out of plasma into the fluids and tissues of the body. It decides where the drug can act, how quickly the effect begins and how long it lasts, and it explains why a compound that works well in a dish can fail in a living animal.
The lecture measures it with one derived number, the apparent volume of distribution, and asks students to calculate it, interpret it and use it to set a loading dose.
The body as a set of water compartments
Total body water in an adult is about 60 per cent of body weight, some 42 litres.
Roughly 28 litres sits inside cells and 14 litres outside them, and of the extracellular part about 10.5 litres is interstitial fluid and 3 litres is plasma.
Drugs sort themselves among these spaces according to their properties: ethanol spreads through all body water, gentamicin stays in extracellular water, antibodies remain largely in plasma, diazepam concentrates in fat, and lead and fluoride collect in bone.
The properties that move a drug
Lipid solubility is the first.
Lipid-soluble drugs cross cell membranes, the placenta and the blood-brain barrier, give large volumes and may accumulate in fat, which is why obese patients recover more slowly from anaesthesia. Lipid-insoluble drugs remain outside cells. Tissue binding creates reservoirs that lower plasma concentration and can prolong action or toxicity.
Plasma protein binding holds drug in the circulation; only the unbound fraction acts, so displacement by a second drug or a fall in albumin can raise the active concentration sharply.
Blood flow determines the order in which tissues fill, from brain, liver and kidney through muscle and skin to fat and bone.
What the volume of distribution is, and is not
Vd is the volume that would hold the total amount of drug in the body at the plasma concentration. Because it is a ratio, a very low plasma level produces a very large volume even when the patient's real fluid volume is unchanged.
The lecture's rule is to read it relatively: a large value means wide distribution or sequestration, a small value means limited distribution, and neither identifies a specific tissue. Its practical use is the loading dose, the target concentration multiplied by Vd and divided by bioavailability.
Compartment models
A pharmacokinetic compartment is a mathematical space rather than an organ.
The single-compartment model treats the body as one uniformly mixed volume. Multi-compartment models allow a central compartment of plasma and well-perfused organs to exchange drug with peripheral tissue over time, which is how the lecture explains an in vivo failure despite strong in vitro potency.
What this chapter covers
- 01
Total body water and its intracellular, interstitial and plasma compartments
- 02
Lipid solubility, redistribution and passage across the placenta and blood-brain barrier
- 03
Tissue binding as a drug reservoir and a source of organ toxicity
- 04
Plasma protein binding, displacement interactions and hypoalbuminaemia
- 05
Blood flow and the order in which tissues receive drug
- 06
Apparent volume of distribution: calculation and interpretation
- 07
Loading dose from target concentration, volume and bioavailability
Worked example · free
Interpreting a volume of distribution before dosing
- 2Express the volume per kilogram and compare it with the compartments.
- 1Calculate the intravenous loading dose.
- 1State what the volume cannot tell you.
Key terms
- Volume of Distribution
- The apparent volume that would contain the total amount of drug in the body at the same concentration as in plasma.
- Total Body Water
- About 60 per cent of body weight, roughly 42 litres in an adult, divided between intracellular and extracellular fluid.
- Redistribution
- Movement of a lipid-soluble drug from well-perfused organs to muscle and then fat, which can end its action.
- Tissue Binding
- Reversible attachment of drug to proteins, phospholipids, fat or bone in tissues, creating a reservoir outside plasma.
- Plasma Protein Binding
- Reversible attachment of drug to albumin or alpha-1 acid glycoprotein, leaving only the free fraction active.
- Loading Dose
- A dose calculated from target concentration and volume of distribution to reach that concentration quickly.
- Compartment Model
- A mathematical space in which a drug is assumed to distribute uniformly, not necessarily matching any organ.
Drug Distribution and Volume of Distribution FAQ
Can a drug really have a volume of distribution of hundreds of litres?
The number can be that large, but the patient does not contain that much fluid. A large Vd arises when most of the dose leaves plasma for fat, muscle, bone or intracellular sites, so the plasma concentration used as the denominator is very small and the calculated ratio becomes huge.
Why do obese patients take longer to wake after some anaesthetics?
Drugs such as thiopentone and propofol are highly lipid soluble and accumulate in adipose tissue. The enlarged fat compartment acts as a reservoir that releases drug slowly back into the circulation, prolonging sedation and delaying recovery after surgery.
Why is hypoalbuminaemia dangerous for a highly bound drug?
With less albumin available, a smaller fraction of the drug is bound and more circulates free. Free drug is the active form and is also what distributes into tissue, so toxicity and interaction risk rise, as with warfarin in cirrhosis or malnutrition.
How can aminoglycoside toxicity occur when plasma levels look acceptable?
With repeated doses the drug binds and accumulates in the renal cortex and inner ear. Those tissues act as reservoirs, so nephrotoxicity and ototoxicity can develop and persist even after plasma concentrations decline, and plasma monitoring can underestimate tissue exposure.
Why might a drug for Alzheimer's disease reach high plasma levels yet do nothing in the brain?
It may fail to cross the blood-brain barrier because of low lipid solubility, high ionisation or excessive protein binding. The course's lesson for drug development is to measure brain-to-plasma ratio and brain exposure rather than relying on plasma concentration.
Does dehydration change drug levels even at a standard dose?
Yes. Dehydration shrinks the fluid compartments, mainly extracellular fluid, which lowers the apparent volume of distribution. The same weight-based dose then produces a higher plasma concentration, which is how the course's dehydrated toddler developed early toxicity.
Exam move
Memorise four landmark volumes per kilogram, 0.04, 0.2, 0.6 and anything well above that, with one example drug for each. Every Vd question then becomes a comparison against a landmark followed by one multiplication for the loading dose.
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