How does first-pass metabolism influence oral bioavailability?

• A. It increases the fraction of unchanged chemical reaching systemic circulation.
• B. It has no effect on oral bioavailability.
• C. It reduces the fraction of unchanged chemical reaching systemic circulation, lowering oral bioavailability.
• D. It only affects inhalation exposures.

Answer: (C)

First-pass metabolism refers to the metabolism a drug undergoes in the gut wall and liver after it's absorbed from the gastrointestinal tract, before it reaches the bloodstream. Enzymes in these tissues (like intestinal and hepatic enzymes) convert the drug into metabolites, so the amount that remains unchanged and available to reach systemic circulation is reduced. Oral bioavailability is the fraction of an oral dose that reaches systemic circulation unchanged, so when first-pass metabolism is active, this fraction decreases, lowering oral bioavailability. Some drugs are highly susceptible to this effect and show very low oral bioavailability as a result, whereas non-oral routes or drugs designed to bypass or minimize first-pass metabolism can achieve higher bioavailability. The option referencing inhalation exposures isn’t applicable to the oral route, and the notion that first-pass would increase the unchanged fraction contradicts the mechanism.