Which statement about hepatic clearance is true when fu increases for a drug with non-saturable intrinsic clearance?

• A. CLh decreases
• B. CLh is zero
• C. CLh becomes unpredictable
• D. CLh increases toward hepatic blood flow limit

Answer: (D)

Hepatic clearance depends on both the liver’s blood flow and the liver’s intrinsic ability to metabolize the drug, with only the unbound fraction of drug (fu) available for metabolism. For a drug with non-saturable intrinsic clearance, the well-stirred model gives CLh = (Qh × fu × Clint,u) / (Qh + fu × Clint,u). Here Clint,u is the intrinsic clearance by the liver when the drug is unbound.

As fu increases, more drug is free to be metabolized, so CLh rises. However, it cannot rise without bound: it approaches the hepatic blood flow limit (Qh) because once the amount of drug reaching the liver is large enough relative to the liver’s capacity, the rate is limited by blood flow, not by metabolic capacity. Therefore, increasing fu raises CLh toward Qh, making the statement that CLh increases toward the hepatic blood flow limit the best description.