If a drug has a high hepatic extraction ratio, what primarily limits its clearance?

If a drug has a high hepatic extraction ratio, what primarily limits its clearance?

• A. Enzyme capacity (CLint).
• B. Hepatic blood flow.
• C. Renal function.
• D. Plasma protein binding.

Answer: (B)

When a drug has a high hepatic extraction ratio, the liver removes most of the drug in a single pass as blood flows through it. In this situation the rate at which the drug can be cleared from the body is governed by how much blood can deliver drug to the liver per unit time, i.e., hepatic blood flow. So the clearance becomes flow-limited, approaching the value of hepatic blood flow itself. The enzyme capacity (intrinsic clearance) matters more when extraction is not near 1; with high extraction, increasing metabolic capacity won’t substantially raise clearance because the bottleneck is delivery, not metabolism. Renal function isn’t involved in hepatic clearance, and while plasma protein binding reduces the amount of free drug available for metabolism, the dominant limiting factor here is blood flow to the liver.

When a drug has a high hepatic extraction ratio, the liver removes most of the drug in a single pass as blood flows through it. In this situation the rate at which the drug can be cleared from the body is governed by how much blood can deliver drug to the liver per unit time, i.e., hepatic blood flow. So the clearance becomes flow-limited, approaching the value of hepatic blood flow itself. The enzyme capacity (intrinsic clearance) matters more when extraction is not near 1; with high extraction, increasing metabolic capacity won’t substantially raise clearance because the bottleneck is delivery, not metabolism. Renal function isn’t involved in hepatic clearance, and while plasma protein binding reduces the amount of free drug available for metabolism, the dominant limiting factor here is blood flow to the liver.