What does a high hepatic extraction ratio indicate about drug clearance?

• A. A high extraction ratio indicates absorption-limited clearance.
• B. A high hepatic extraction ratio indicates clearance approaches liver blood flow and is flow-limited; low-ER is capacity-limited.
• C. High ER implies negligible clearance.
• D. ER is unrelated to hepatic clearance.

Answer: (B)

A high hepatic extraction ratio means the liver removes a large fraction of the drug from the blood as it passes through. In PK terms, hepatic clearance equals liver blood flow times the extraction ratio (CL_H = Q_h × ER). When ER is near 1, clearance approaches the rate of hepatic blood flow, so the process is flow-limited rather than limited by the liver’s metabolic capacity. In other words, the bottleneck is how fast blood delivers drug to the liver, not how fast the liver can metabolize it. If ER were low, clearance would be capacity-limited and governed by intrinsic metabolic ability. This does not reflect absorption, and it certainly does not imply negligible clearance.