presystemic

Presystemic describes processes that affect a substance before it reaches systemic circulation. In pharmacology, presystemic metabolism and elimination reduce the fraction of an orally administered drug that enters the bloodstream, a phenomenon commonly called the first-pass effect. Presystemic events can occur in the gastrointestinal tract, the intestinal wall, and the liver, and may also involve gut microbiota or chemical degradation within the lumen.

Mechanisms include enzymatic metabolism in the intestinal mucosa, such as cytochrome P450 enzymes and UDP-glucuronosyltransferases, as well as phase II conjugation and hydrolysis. The gut microbiota can degrade or modify drugs before absorption. After portal absorption, hepatic metabolism also contributes to presystemic processing. These steps lower oral bioavailability and can generate metabolites that contribute to effects or toxicity.

Clinical relevance and factors: presystemic metabolism influences dosing, formulation, and route of administration. Strategies to bypass or reduce it include alternative delivery routes (sublingual, transdermal, intravenous), prodrug design to improve absorption, or concomitant use of enzyme inhibitors. Drug properties such as lipophilicity, stability, and permeability, along with patient factors (age, liver function, gut microbiome, concomitant medications), determine the extent of presystemic processing.

Overview: The term is widely used in pharmacokinetics and drug development, where understanding presystemic effects helps predict systemic exposure, therapeutic efficacy, and safety. It is closely related to the first-pass effect and bioavailability concepts.