If fu increases while CLint and Qh remain fixed, what is the expected effect on hepatic clearance CLh according to the well-stirred model?

• A. CLh decreases.
• B. CLh remains unchanged.
• C. CLh increases.
• D. CLh becomes negative.

Answer: (C)

In the well-stirred hepatic clearance model, CLh depends on the unbound intrinsic clearance CLint,u = fu × CLint and the hepatic blood flow Qh, with CLh = (Qh × CLint,u) / (Qh + CLint,u). If CLint and Qh are fixed and fu increases, CLint,u increases proportionally, so CLh rises as well. When CLint,u is small compared with Qh, CLh ≈ CLint,u, meaning clearance climbs roughly with fu. As CLint,u becomes large relative to Qh, CLh approaches Qh and cannot exceed it, so the increase slows and saturates. Thus increasing fu leads to higher hepatic clearance, up to the limit set by hepatic blood flow.