What is the Origin of First-Pass Effect?

The term emerged from the field of pharmacology in the mid-20th century as scientists sought to explain the unexpectedly low systemic concentrations of certain orally administered compounds. It describes the drug's initial passage through the portal venous system and the liver's profound metabolic filtering capacity. Understanding the first-pass effect is fundamental to the rational design of drug delivery systems and dosage forms, guiding the choice between oral and non-oral routes.

What is the Mechanism of First-Pass Effect?

The process initiates when a drug is absorbed from the gastrointestinal tract and enters the hepatic portal vein, transporting it directly to the liver, the principal site of drug metabolism. Hepatocytes contain numerous Phase I and Phase II metabolizing enzymes, such as cytochrome P450, which rapidly convert the active compound into inactive or less active metabolites. The fraction of the original dose that survives this hepatic metabolism is what ultimately enters the general circulation to elicit a therapeutic effect.

First-Pass Effect

Meaning

The First-Pass Effect, or pre-systemic metabolism, is a critical pharmacokinetic phenomenon describing the extensive metabolism of an orally administered drug before it reaches the systemic circulation. This reduction in bioavailability occurs primarily in the liver, where a high concentration of enzymes rapidly inactivates a portion of the drug dose. For many steroid hormones, this effect significantly limits the amount of active compound that can reach target tissues throughout the body. Clinicians must account for this phenomenon when determining appropriate oral dosing regimens to ensure therapeutic efficacy.