First pass effect

The first-pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation. It is the fraction of lost drug during the process of absorption which is generally related to the liver and gut wall. Notable drugs that experience a significant first-pass effect are imipramine, morphine, propranolol, buprenorphine, diazepam, midazolam, demerol, cimetidine, and lidocaine.

After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body. The liver metabolizes many drugs, sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system. This first pass through the liver thus greatly reduces the bioavailability of the drug. Alternative routes of administration like suppository, intravenous, intramuscular, inhalational aerosol, transdermal and sublingual avoid the first-pass effect because they allow drugs to be absorbed directly into the systemic circulation. Note that the intravenous route also avoids the absorption phase.

The four primary systems that affect the first pass effect of a drug are the enzymes of the gastrointestinal lumen, gut wall enzymes, bacterial enzymes, and hepatic enzymes.

In drug design, drug candidates may have good druglikeness but fail on first-pass metabolism, because it is biochemically selective.

References and external links

 * National Library of Medicine, Toxicology Tutor II, Influence of Route of Exposure
 * University of Nottingham School of Nursing, Reusable Learning Objects--Understanding First Pass Metabolism