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First-pass metabolism and bioavailability

المؤلف:  Sue Jickells , Adam Negrusz (Editors)

المصدر:  Clarkes Analytical Forensic Toxicology

الجزء والصفحة:  p15-16

2026-09-13

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First-pass metabolism and bioavailability

Drugs may be destroyed by the acid in the stomach or by enzymes in the gastrointestinal tract, or may hardly be absorbed at all because of their chemical nature. These factors reduce the drug’s bioavailability. Drugs absorbed after oral ingestion pass through the mesenteric circulation into the liver before they enter the systemic circulation. In this ‘first-pass’, drugs can be substantially metabolised by the liver before ever having a pharmacological effect. The proportion of the drug that reaches the systemic circulation after oral administration compared to that obtained after intravenous dosing is the oral (or absolute) bioavailability (F). This is measured by com paring the area under the curve (AUC) for the oral and intravenous doses from time zero to the time-point at which most or all of the drug is finally eliminated by the body. The formula is:

where AUC (the area under the plasma concentration–time curve)  represents the amount of drug that enters the systemic circulation from time zero to infinite time for each route of administration. The relative bioavailabilities of drugs can be determined by comparing other routes of admin istration with oral or another reference route of administration, or between drug formulations. The oral bioavailabilities of selected drugs are shown in Table 2.1. In general, drugs that are readily metabolised by liver enzymes have lower bioavailabilities than drugs that are not metabolised as readily by the liver. Some drugs are metabolised in the liver to active forms. While the effect of first-pass metabolism is to reduce the action of the parent drug, a drug that is administered orally and metabolised in the liver to active forms has a different profile of activity from that when the drug is given parenterally (not through the gastrointestinal system). For example, when cannabis is consumed orally (cookies), THC is converted in the liver to the 11-hydroxy metabolite, which is active and hence exerts a significant drug effect. When cannabis is smoked, first-pass metabolism of THC to the 11-hydroxy metabolite is markedly reduced and effects due to the metabolite are less. Some drugs which are activated by liver metabolism are administered as pro-drugs, with oral administration of the pro-drug preferred to other routes of administration to maximise the activity of the drug. An example is enalapril, which is converted into enalaprilic acid. The latter form is much more active than the parent drug. Drugs given rectally are subject to only a small degree of first-pass metabolism, since only about one-third of the blood supply from the lower part of the gastrointestinal system passes though the liver.