Pharmacokinetics
Free Fraction fu
The proportion of total plasma drug concentration that is unbound — pharmacologically active, available for distribution to target tissues, and eligible for hepatic metabolism and renal elimination. Changes in protein binding alter free drug exposure without affecting measured total concentration.
Definition and Equation
Drugs in plasma exist in two forms: bound to plasma proteins (primarily albumin and α1-acid glycoprotein) and unbound (free). Only unbound drug:
- Crosses biological membranes to reach target tissue receptors
- Exerts pharmacological effects (receptor binding, enzyme inhibition)
- Is available for hepatic metabolism (CYP enzyme substrate)
- Is filtered at the glomerulus (for renal clearance)
fu = Cunbound / Ctotal = 1 − fb
Where fb = fraction bound. For a drug that is 98% protein-bound, fu = 0.02 (only 2% is free and pharmacologically active). Reference: NCBI StatPearls: pharmacokinetics ↗; Benet & Hoener, Clin Pharmacol Ther (PubMed) ↗.
Binding Proteins and Clinical Conditions Altering fu
| Protein | Binds | ↓ in | ↑ in |
|---|---|---|---|
| Albumin | Acidic drugs (warfarin, NSAIDs, phenytoin, valproate, diazepam) | Liver failure, nephrotic syndrome, malnutrition, sepsis, burns | Not clinically relevant |
| α1-acid glycoprotein (AAG) | Basic drugs (lidocaine, propranolol, amitriptyline, methadone) | Neonates, pregnancy, oral contraceptive use | Inflammation, surgery, MI, renal failure, cancer |
Clinical Implications for TDM and Dosing
- Phenytoin in hypoalbuminaemia: albumin falls in critical illness, nephrotic syndrome, liver disease. Standard total phenytoin therapeutic range (10–20 mg/L) does not apply. Measure free phenytoin (1–2 mg/L) or use the Sheiner-Tozer correction. See Michaelis-Menten kinetics for phenytoin non-linear PK context.
- Valproic acid: protein binding is saturable at therapeutic concentrations; free fraction increases non-linearly as total concentration rises. Also displaced by aspirin and carbamazepine. Measure free valproate in high-dose therapy or renal failure.
- Warfarin: >99% albumin-bound (fu ≈ 0.005). In elderly patients with low albumin, free warfarin fraction rises — increased anticoagulant effect at lower total doses. See anticoagulant guide and polypharmacy in older adults.
- Intrinsic clearance and fu interaction: for low-extraction drugs, CLH = fu × CLint. A drop in albumin (↑fu) increases hepatic clearance of capacity-limited drugs while simultaneously increasing free concentrations at tissues — net effect depends on which change dominates. See intrinsic clearance and extraction ratio.
NCBI StatPearls: therapeutic drug monitoring ↗; PubMed: fu and TDM ↗.
FAQ
What is free fraction (fu)?
Free fraction (fu) is the proportion of total drug concentration in plasma that exists as unbound (free) drug. fu = Cunbound / Ctotal = 1 − fraction bound. Only unbound drug crosses biological membranes, exerts pharmacological effects, and is available for hepatic metabolism and renal filtration. A drug with fu = 0.01 is 99% protein-bound; only 1% is free and pharmacologically active.
Why does free fraction matter for dosing and drug monitoring?
Standard therapeutic drug monitoring (TDM) typically measures total drug concentration (bound + free). For drugs that are highly protein-bound, changes in protein binding — due to hypoalbuminaemia, renal failure, or drug displacement interactions — can substantially alter free drug concentration without changing the measured total concentration. This can lead to toxicity at total concentrations that appear within the therapeutic range. Measuring free (unbound) concentrations is essential for phenytoin in hypoalbuminaemia, valproic acid in renal failure, and other highly bound drugs with narrow therapeutic indices.
Which plasma proteins bind drugs, and what affects binding capacity?
Albumin (35–50 g/L in healthy adults) is the principal binding protein for acidic drugs (NSAIDs, warfarin, phenytoin, valproic acid) and many neutral drugs. Alpha-1-acid glycoprotein (AAG, also called orosomucoid) binds basic drugs (lidocaine, propranolol, amitriptyline, methadone). AAG is an acute-phase reactant — levels rise in inflammation, surgery, myocardial infarction, and cancer, reducing free fraction of basic drugs. Albumin falls in liver disease, nephrotic syndrome, malnutrition, and critical illness — increasing free fraction of acidic drugs.
What is the Sheiner-Tozer equation and when is it used?
The Sheiner-Tozer equation corrects the measured total phenytoin concentration for reduced albumin levels, estimating the concentration that would be measured if albumin were normal. In patients with hypoalbuminaemia, phenytoin free fraction increases, so the "normal" total therapeutic range (10–20 mg/L) overestimates the required dose. The equation: Adjusted phenytoin = Measured total phenytoin / [(0.2 × albumin g/dL) + 0.1]. In renal failure (GFR < 10 mL/min), a different factor is used: Adjusted = Measured / [(0.1 × albumin) + 0.1], because uraemic acids also displace phenytoin from albumin. Direct measurement of free phenytoin (therapeutic range 1–2 mg/L) is preferable when available.