Which statement about high extraction ratio drugs is true?

• A. Their hepatic clearance is largely determined by hepatic blood flow
• B. They are only limited by intrinsic clearance
• C. They are unaffected by protein binding
• D. They have negligible hepatic clearance

Answer: (A)

High extraction ratio drugs are cleared as fast as the liver can deliver them, so clearance is limited by hepatic blood flow rather than by the liver’s enzyme capacity. In the standard liver model, CLh = (Qh × fu × Clint) / (Qh + fu × Clint). When fu × Clint is very large compared with Qh, CLh ≈ Qh, meaning the rate at which blood enters the liver dictates how fast the drug is cleared. This flow-limited behavior is why the statement that hepatic clearance is largely determined by hepatic blood flow is the true one for high extraction drugs.

The other ideas don’t fit this picture. If intrinsic clearance were the sole limiter, clearance would track Clint rather than flow. Protein binding can affect fu and thus Clint, so it isn’t completely irrelevant, even if the impact is smaller when flow is the bottleneck. And hepatic clearance for high extraction drugs isn’t negligible; it can be substantial and approach the value of hepatic blood flow.