Bioavailability is defined as the fraction of an orally administered drug that reaches systemic circulation. How does first-pass hepatic metabolism affect oral bioavailability and dosing?

• A. It reduces the fraction reaching systemic circulation due to hepatic metabolism.
• B. It has no effect on oral bioavailability.
• C. It increases oral bioavailability above the administered dose.
• D. It only affects drugs given intravenously.

Answer: (A)

The amount of drug that reaches systemic circulation after an oral dose is reduced by first-pass hepatic metabolism. After absorption from the gut, the drug travels through the portal vein to the liver, where hepatic enzymes metabolize a portion before it can circulate systemically. This initial liver processing lowers oral bioavailability, meaning a larger oral dose may be needed to achieve the same systemic exposure as an intravenous dose, or an alternative route that bypasses the liver may be used. Drugs with extensive first-pass effect have notably low oral bioavailability, which is why dosing often differs between oral and parenteral administration.