14.2 Distribution & Protein Binding

Volume of Distribution

After IV injection, drug distributes between plasma and tissues. The (apparent) volume of distribution (Vd) relates the amount of drug in the body to the measured plasma concentration:

Vd = Amount of drug in body ÷ Plasma concentration = Dose ÷ Cp₀ (for an IV bolus, where Cp₀ is the extrapolated concentration at time zero)

Worked example: A 500 mg IV bolus produces an extrapolated Cp₀ of 20 mg/L.

Vd = 500 mg ÷ 20 mg/L = 25 L

Vd is apparent, not anatomical — it is the volume that would be required to contain the total body drug at the measured plasma concentration. It is best expressed per kilogram (L/kg) and compared with body water compartments: plasma ≈ 0.07 L/kg, extracellular fluid ≈ 0.2 L/kg, total body water ≈ 0.6 L/kg.

Interpreting small versus large Vd

Rules of thumb:

• Small Vd (<0.3 L/kg): hydrophilic or highly protein-bound drug; plasma levels respond strongly to dose changes; more readily removed by dialysis.
• Large Vd (>1 L/kg): lipophilic or extensively tissue-bound drug; dialysis is ineffective in overdose; loading doses must be large.

Physiological determinants of Vd

• Lipophilicity — lipophilic drugs leave plasma and enter fat and tissue (large Vd).
• Tissue binding — e.g., digoxin to muscle Na⁺/K⁺-ATPase; tetracyclines to growing bone and teeth.
• Plasma protein binding — extensive binding retains drug in plasma (small Vd).
• Patient factors — age, sex and body composition (elderly patients have less body water, so hydrophilic drugs such as digoxin reach higher concentrations); oedema and ascites increase the Vd of hydrophilic drugs.

One-Compartment versus Two-Compartment Models

In a one-compartment model the body behaves as a single, instantly mixing tank: the log plasma concentration–time plot after an IV bolus is a straight line with a single elimination slope. In a two-compartment model, plasma concentration falls biexponentially:

1. a rapid distribution (alpha) phase as drug moves from plasma (central compartment) into well-perfused tissues, followed by
2. a slower elimination (beta) phase once pseudo-equilibrium is reached.

This matters clinically: with drugs such as digoxin, plasma sampled during the distribution phase is misleadingly high — draw levels at least 6 hours post-dose.

Plasma Protein Binding

In plasma, drugs exist in equilibrium between bound (inactive, non-diffusible) and free (unbound) fractions. Only the unbound drug can distribute, bind receptors, be metabolized and be filtered at the glomerulus.

• Albumin binds mainly acidic drugs: warfarin (~99% bound), phenytoin (~90%), NSAIDs, sulfonamides, valproate.
• Alpha-1 acid glycoprotein (AAG) binds mainly basic drugs: lidocaine, propranolol, imipramine, quinidine. AAG is an acute-phase reactant — it rises in inflammation and trauma, lowering the free fraction of basic drugs.

Displacement interactions

One highly bound drug can displace another from albumin, transiently raising the free, active fraction. The classic historical example is phenylbutazone displacing warfarin — a sharp rise in free warfarin with bleeding risk (phenylbutazone also inhibits warfarin metabolism, amplifying and prolonging the effect). Similarly, valproate displaces phenytoin and inhibits its metabolism, so total phenytoin may fall while free (active) phenytoin rises — monitor free levels, not just total.

Displacement interactions are clinically important only when all of the following hold:

1. the displaced drug is >90% protein bound (a small displaced fraction is then relatively large),
2. it has a small volume of distribution (displaced drug stays near plasma), and
3. it has a narrow therapeutic index (warfarin, phenytoin).

Even then, the rise in free drug is usually transient: more free drug is also more available for metabolism and excretion, so a new steady state is reached — unless clearance is simultaneously inhibited.

Hypoalbuminemia and the Phenytoin Correction

Low albumin — in nephrotic syndrome, liver failure, malnutrition, pregnancy, the elderly, burns and critical illness — increases the free fraction of highly bound acidic drugs. The total measured concentration then underestimates pharmacological activity. The trap drug is phenytoin: a 'low-normal' total level in a hypoalbuminemic patient may conceal a therapeutic or even toxic free level.

The Sheiner-Tozer equation estimates what the total phenytoin level would be at normal albumin:

Adjusted total phenytoin = Measured total ÷ [(0.2 × albumin in g/dL) + 0.1]

(Use 0.25 instead of 0.2 when renal function is severely impaired.)

Worked example: measured total phenytoin 8 mg/L, serum albumin 2.0 g/dL:

1. Denominator = (0.2 × 2.0) + 0.1 = 0.5
2. Adjusted level = 8 ÷ 0.5 = 16 mg/L — comfortably within the usual 10–20 mg/L target range, despite the apparently subtherapeutic raw result. Where available, a directly measured free (unbound) phenytoin (target 1–2 mg/L) is preferable.

Barriers to Distribution

• Blood-brain barrier (BBB): tight junctions between capillary endothelial cells plus P-glycoprotein efflux. Only small, lipophilic, unionized drugs cross readily — levodopa does, dopamine does not, hence levodopa (not dopamine) is used in Parkinson's disease. Meningeal inflammation partly disrupts the barrier, which is why penicillins achieve therapeutic CSF levels in bacterial meningitis.
• Placenta: behaves like a lipid barrier — lipophilic, unionized drugs (including most general anaesthetics and opioids) cross freely; large polar molecules (e.g., heparin) do not. For most small molecules the placenta is a sieve, not a shield.

Loading Dose

To reach a therapeutic concentration immediately rather than waiting ~4–5 half-lives for accumulation:

Loading dose = (Vd × target plasma concentration) ÷ F

Worked example — digoxin (70 kg adult, target 1 µg/L, Vd ≈ 7 L/kg, IV so F = 1):

1. Vd = 7 × 70 = 490 L
2. Loading dose = 490 L × 1 µg/L = 490 µg ≈ 0.5 mg (in practice given in divided doses, and rounded to available strengths if oral, where F ≈ 0.7)

Note that the loading dose depends on Vd, not clearance — clearance governs the maintenance dose (Section 14.3).