How does first-pass metabolism affect oral bioavailability and AUC?

• A. It increases F and AUC
• B. It has no effect on F or AUC
• C. It reduces F and lowers AUC
• D. It reduces F but increases AUC

Answer: (C)

First-pass metabolism reduces the amount of unchanged drug that reaches the systemic circulation. Because the oral bioavailability (F) is the fraction of the dose that survives gut and liver metabolism to appear in the blood, this process lowers F. The overall exposure after an oral dose, quantified by AUC, is proportional to F (for a given dose and clearance). So when first-pass metabolism lowers F, the AUC after oral dosing also decreases. In standard cases, this means both oral bioavailability and AUC are reduced. (Only in rare situations where active metabolites contribute substantially to systemic exposure would total exposure outside the parent drug differ, but the basic relationship remains: first-pass metabolism lowers F and lowers AUC.)