For a high extraction liver drug, which statement is true about hepatic clearance (CLh) relative to hepatic blood flow (Qh) and intrinsic clearance (CLint)?

• A. If intrinsic clearance is high, hepatic clearance approaches hepatic blood flow.
• B. CLh is always less than Qh regardless of CLint.
• C. CLh equals CLint regardless of perfusion.
• D. CLh can exceed Qh.

Answer: (A)

For high extraction drugs, clearance by the liver is limited by how quickly blood can deliver drug to the liver, not by the enzyme’s capacity. In the well-stirred liver model, CLh = Qh × Eh, where Eh = (CLint × fu) / (Qh + CLint × fu). If intrinsic clearance times the unbound fraction is very large compared with hepatic blood flow, Eh approaches 1, so CLh ≈ Qh. That means the liver’s clearance effectively matches hepatic blood flow when the enzyme system is very capable.

So the statement that best fits is that hepatic clearance approaches hepatic blood flow when intrinsic clearance is high. The other possibilities don’t fit: CLh cannot exceed Qh, and CLh is not equal to CLint regardless of perfusion; instead, CLh tends toward CLint × fu in low-perfusion (low extraction) situations and toward Qh in high-perfusion (high extraction) situations.