FirstpassMetabolismus

First-pass metabolism refers to the hepatic and, to a lesser extent, intestinal metabolism of a drug after it is absorbed from the gastrointestinal tract but before it reaches the systemic circulation. After oral administration, the drug is carried via the portal vein to the liver, where enzymes such as cytochrome P450s and conjugation systems (e.g., UGT, sulfotransferases) can modify the compound. This pre-systemic metabolism can greatly reduce the amount of active drug that reaches the general circulation, a phenomenon known as limited oral bioavailability.

The extent of first-pass metabolism depends on the drug’s intrinsic clearance, hepatic blood flow, and extraction ratio. Drugs with high hepatic extraction ratios typically show low oral bioavailability because a large fraction is metabolized during the first pass. Examples include morphine, propranolol, and lidocaine, while nitroglycerin is often inactivated almost completely by the liver, explaining why non-oral routes are used for some agents.

Routes that bypass first-pass metabolism include sublingual and buccal administration, transdermal delivery, intravenous injection, inhalation, and, to a lesser extent, rectal administration. In drug development, formulations may be designed to avoid first-pass effects or to exploit them (as with certain prodrugs that release the active compound after hepatic processing).

Various factors influence the magnitude of first-pass metabolism, including hepatic blood flow, enzyme activity and expression (influenced by genetics, age, and disease), concomitant medications that inhibit or induce metabolic enzymes, and food interactions. Clinically, understanding first-pass metabolism informs dosing decisions, route selection, and the potential for drug–drug interactions, contributing to interindividual variability in response.