Volume of distribution at steady state
Vss Pharmacokinetics Distribution
The total apparent volume in which a drug is distributed at steady state, equal to the sum of central and peripheral compartment volumes. Vss is the theoretically correct parameter for multi-compartment drugs, unlike Vd(β) which is influenced by elimination.
Volume of Distribution Estimates Compared
| Parameter | Formula | Relative size | Notes |
|---|---|---|---|
| Vc (central) | Dose / C₀ | Smallest | Plasma + rapidly equilibrating tissues only; time = 0 |
| Vss | CL × MRT | Intermediate | True steady-state volume; sum of all compartments; independent of elimination |
| Vd(β) / Vd(area) | Dose / (AUC × β) | Largest | Inflated by terminal elimination slope; overestimates true distribution |
For a two-compartment drug: Vc < Vss < Vd(β). The three values converge for one-compartment drugs.
Formulas
Vss = CL × MRT
Vss = Vc + Vt (sum of central and peripheral compartments)
MRT = AUMC / AUC (from IV bolus data)
Loading dose = Vss × Ctarget / F
Vss = Vc + Vt (sum of central and peripheral compartments)
MRT = AUMC / AUC (from IV bolus data)
Loading dose = Vss × Ctarget / F
AUMC is the area under the first moment of the plasma concentration-time curve. Vss can be calculated from non-compartmental analysis without assuming a specific compartment model.
~5000 L
Amiodarone Vss
Extreme tissue binding
~250–800 L/kg
Chloroquine Vss
Lysosomal trapping
~8 L
Warfarin Vss
Predominantly plasma-bound
~0.25 L/kg
Gentamicin Vss
Hydrophilic, ECF only
CL × MRT
Vss formula
Non-compartmental calculation
Vss ≤ Vd(β)
Vss vs Vd(β)
Always true for multi-comp
Clinical Applications
- Loading dose calculation: Loading dose = Vss × Ctarget / F. For digoxin (Vss ~7 L/kg, 70 kg patient = 490 L), achieving Ctarget 1.5 mcg/L requires LD ≈ 735 mcg (IV, F=1).
- Dialysis removal: Drugs with large Vss are not efficiently removed by dialysis — the drug is distributed beyond plasma and cannot be rapidly cleared. Amiodarone (Vss 5000 L) is not dialysable.
- Lipophilicity prediction: Vss > 1 L/kg suggests moderate to extensive tissue distribution; > 10 L/kg suggests very high lipophilicity or active tissue uptake.
- Altered physiology: Oedema/ascites increases Vss for hydrophilic drugs; low albumin increases Vss for highly protein-bound drugs; obesity increases Vss for lipophilic drugs.