For a drug with a low hepatic extraction ratio (E < 0.3), which change would MOST increase its hepatic clearance?

• A An increase in hepatic blood flow
• B Co-administration of a potent CYP inhibitor
• C An increase in free (unbound) fraction of drug in plasma together with preserved intrinsic clearance ✓
• D Development of a portosystemic shunt

Explanation

By the well-stirred model, clearance of a low-extraction drug depends mainly on intrinsic metabolic capacity (Clint) and the unbound fraction (fu), and is relatively insensitive to hepatic blood flow. Increasing fu delivers more diffusible drug to enzymes and raises clearance. Option A matters chiefly for high-extraction drugs. Option B reduces Clint and therefore lowers clearance. A portosystemic shunt diverts drug away from hepatic metabolism and reduces systemic clearance.

Reference: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 14th ed.

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