What is the unbound (free) fraction fu, and why is it pharmacokinetically important?

• A. Fu is the fraction bound to plasma proteins; it is inactive, and determines distribution to tissues.
• B. Fu is the fraction unbound to plasma proteins; it is pharmacologically active, determines distribution into tissues, and influences clearance and drug interactions.
• C. Fu is the fraction of drug excreted renally.
• D. Fu is the fraction metabolized by the liver.

Answer: (B)

In pharmacokinetics, fu is the fraction of drug in the plasma that remains unbound to plasma proteins such as albumin and alpha-1 acid glycoprotein. This unbound portion is pharmacologically active because it is free to cross capillary membranes, reach targets, be metabolized by enzymes, and be filtered by the kidneys. Since only the unbound drug can distribute into tissues and be cleared, fu directly influences both distribution and clearance, and it also affects drug–drug interactions when one drug displaces another from protein binding, raising the free concentration. The portion that is bound serves mainly as a reservoir and is not immediately active or cleared, so it does not drive the pharmacologic effect or elimination. Thus, describing fu as the fraction unbound to plasma proteins, being pharmacologically active, and governing distribution, clearance, and interactions captures why it is pharmacokinetically important. The other descriptions refer to the bound fraction or to excretion or metabolism, which are different concepts.