For a drug with fixed intrinsic clearance and hepatic blood flow, what is the effect on hepatic clearance when fu increases but CLint is not saturable?

• A. Becomes zero
• B. Decreases
• C. Increases toward Qh
• D. Stays same

Answer: (C)

Under the well-stirred liver model, hepatic clearance depends on the relationship between hepatic blood flow (Qh) and the product of unbound fraction and intrinsic clearance (fu × CLint): CLh = Qh × fu × CLint / (Qh + fu × CLint). If CLint is fixed and not saturable, increasing the fraction unbound (fu) raises fu × CLint, so more drug is available for metabolism. As fu × CLint grows, the clearance moves from being limited by the metabolic capacity toward being limited by blood flow, and CLh approaches Qh. In other words, hepatic clearance increases with fu, but cannot exceed the hepatic blood flow.