How does protein binding influence clearance, especially for hepatic clearance?

• A. Protein binding has no effect on clearance
• B. Only unbound drug (fu) is accessible for clearance; hepatic CLh ∝ fu; high protein binding reduces clearance when Clint is not very high
• C. Higher protein binding always increases clearance
• D. Protein binding affects Vd but not CLh

Answer: (B)

Only unbound drug is available for metabolism and clearance by the liver. In hepatic clearance, the fraction unbound (fu) determines how much drug can be processed, and the well-stirred model ties this to intrinsic clearance (Clint) and hepatic blood flow (Qh) via CLh = Qh × (fu × Clint) / (Qh + fu × Clint).

When Clint isn’t very high, changing fu has a noticeable effect on CLh: increasing fu (reducing protein binding) raises hepatic clearance, while high protein binding lowers it. If Clint is very high relative to Qh, clearance becomes limited by blood flow and changes in fu have little impact, but in typical scenarios with modest Clint, protein binding modulates CLh.

So the best choice captures that hepatic clearance is proportional to fu under these conditions and that strong protein binding lowers clearance when Clint isn’t very high. The other statements misstate the relationship: protein binding does affect clearance, higher binding does not always increase clearance, and binding also influences CLh (not just volume of distribution).