For low extraction ratio drugs, hepatic clearance is primarily limited by which factors?

• A. Hepatic blood flow
• B. Protein binding
• C. Absorption rate
• D. Intrinsic clearance (CLint) and fu

Answer: (D)

The concept being tested is how hepatic clearance behaves for low extraction ratio drugs. When a drug has a low extraction ratio, the amount cleared by the liver is not limited by how fast blood is delivered to the liver, but by the liver’s enzymatic capacity and how much drug is available to be metabolized. The well-known relationship is CLh = (Qh × f_u × CLint) / (Qh + f_u × CLint). If f_u × CLint is much smaller than Qh, this simplifies to CLh ≈ f_u × CLint. So hepatic clearance in this case is governed by the intrinsic clearance (the enzyme’s metabolic capacity) and the unbound fraction of the drug in plasma (fu). Only the unbound drug can be metabolized, so if most of the drug is protein-bound (low fu) or if the intrinsic clearance is low, the overall hepatic clearance will be low.

In other words, for low extraction drugs, the limiting factors are intrinsic clearance and the unbound fraction; hepatic blood flow and absorption rate do not set the clearance to a large extent in this regime.