If fu decreases, what happens to clearance?

• A. Clearance decreases
• B. Clearance increases
• C. No change
• D. Clearance becomes unpredictable

Answer: (A)

The key idea is that only the unbound fraction of a drug (fu) is available for elimination. In the liver, the rate of clearance depends on how much drug is unbound to proteins, because only unbound drug can be metabolized by enzymes and pass through the hepatic processes. For drugs that are not limited by blood flow (low to moderate extraction), hepatic clearance is approximately proportional to fu (CL ≈ fu × CLint in the well-stirred model). So when fu decreases, less drug is free to be cleared, and clearance falls accordingly. That’s why decreasing fu leads to a decrease in clearance in these scenarios. It’s worth noting that for drugs with very high extraction, clearance is largely determined by hepatic blood flow and is less affected by fu, but the common teaching in this context is that lowering fu reduces clearance.