The first-pass effect (also known as first-pass metabolism or presystemic metabolism) refers to the portion of a drug that is lost during the process of metabolism, before it reaches the systemic circulation.

After a drug is ingested, it is absorbed by the digestive system and enters the hepatic portal system. It is transported through the portal vein into the liver before it can be dispersed to the rest of the body. The liver metabolises many drugs; sometimes to such an extent that only a small portion of active drug is sent from the liver to the rest of the circulatory system. This "first pass" through the liver thus greatly reduces the concentration and effectiveness of the drug.

Alternative means of ingestion, such as suppository, intravenous, intramuscular, sublingual (under the tongue) and transdermal sidestep the first-pass effect because they allow drugs to be absorbed directly into the systemic circulation.