Free drug levels are determined by analyzing which sample to reflect the unbound drug concentration?

• A. Whole blood
• B. Ultrafiltrate of plasma
• C. Urine
• D. Protein-free filtrate of plasma

Answer: (B)

The key idea is that only the unbound portion of a drug is pharmacologically active and available for distribution and clearance. To measure this active fraction, you need a sample that contains just the free drug, with proteins and protein-bound drug removed. Ultrafiltration of plasma achieves this by passing plasma through a semipermeable membrane that lets small molecules like the unbound drug through while retaining larger proteins and any drug bound to them. The filtrate therefore reflects the true unbound concentration circulating in plasma.

Whole blood isn’t ideal because it includes cells and may contain drug bound to proteins or components within cells, so it doesn’t represent the free plasma concentration. Urine shows what has been filtered and excreted, which depends on renal handling and not the current unbound plasma level. Protein-free filtrate of plasma could, in theory, isolate unbound drug, but ultrafiltration of plasma is the standard, reliable method used clinically to reflect the unbound concentration.