After oral administration, the drug in the gut lumen may undergo chemical hydrolysis or enzymatic metabolism which is caused primarily by the gut flora. A fraction of the administered dose can be absorbed from the gut lumen and the rest of the dose is excreted unchanged with the feces.

During the absorption process, the drug can be metabolized in the gut wall or excreted back to the gut lumen. Only a fraction of the absorbed dose will reach the portal circulation.

The drug absorbed into the portal vein will have to go through the liver before it reaches the systemic circulation. A fraction of the absorbed dose can be metabolized during this first pass through the liver before it reaches the systemic circulation.

The fraction of the dose that reaches the systemic circulation (bioavailable drug) is the fraction of the dose that escapes hydrolysis and metabolism in the gut lumen, metabolism in the gut wall, and metabolism during the first-pass through the liver. Elimination of the drug before it reaches the systemic circulation is called presystemic elimination or first-pass effect.