An increase in fu typically leads to which of the following?

• A. No change in either parameter
• B. Lower clearance and lower unbound exposure
• C. Higher clearance and higher unbound exposure
• D. Higher clearance but lower unbound exposure

Answer: (C)

When more drug is unbound in plasma, it becomes available for clearance and for distribution to tissues. The unbound portion is the portion that can be eliminated by the liver and kidneys, so increasing the fraction unbound (fu) tends to increase clearance, especially for drugs with low to moderate hepatic extraction where clearance is limited by intrinsic clearance rather than blood flow. In the well-known liver clearance relationship, CL_H rises as fu increases (up to the limit set by hepatic blood flow). At the same time, unbound exposure rises because the unbound concentration is fu times the total concentration. So, in typical cases, increasing fu leads to higher clearance and higher unbound exposure. (For drugs with very high hepatic extraction, the effect of fu on clearance is smaller since clearance is largely limited by blood flow.)