A drug with high hepatic extraction ratio (ER > 0.7) is administered orally. Its oral bioavailability is determined primarily by:
- A Intrinsic hepatic clearance (CLint), since for high-extraction drugs, bioavailability is independent of blood flow and depends only on enzymatic capacity
- B Protein binding, since only unbound drug undergoes first-pass extraction and high-extraction drugs have high free fraction requirements
- C Hepatic blood flow (Q) as the rate-limiting factor, since hepatic clearance approximates Q and first-pass extraction is high regardless of enzyme activity variations ✓
- D Gastrointestinal transit time, since slow absorption exposes more drug to intestinal CYP3A4 before hepatic first-pass
Explanation
For high hepatic extraction ratio drugs (ER > 0.7, e.g., propranolol, morphine, lidocaine), hepatic clearance approximates hepatic blood flow (Clh ≈ Q × ER ≈ Q). Since bioavailability = 1 – ER and ER is primarily determined by blood flow for these drugs, conditions reducing hepatic blood flow (heart failure, portosystemic shunting, liver disease with reduced portal flow) dramatically increase oral bioavailability. Intrinsic clearance determines bioavailability for low-extraction drugs (ER < 0.3), where protein binding and CLint are rate-limiting. This distinction has major implications: liver disease affects high-extraction drug bioavailability through hemodynamic changes, while enzyme inducers/inhibitors mainly affect low-extraction drug clearance.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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