What does bioavailability mean?

Bioavailability is the proportion of an administered dose of unchanged drug that reaches the systemic circulation. By definition an intravenous dose is fully available (100%), and other routes are compared against it.

Why does first-pass metabolism lower oral bioavailability?

After oral absorption, drug passes through the gut wall and liver before entering the general circulation. Enzymes there can metabolise a substantial fraction during this first pass, so less unchanged drug reaches the systemic circulation.

Bioavailability and First-Pass Metabolism

Bioavailability is the fraction of an administered dose of unchanged drug that reaches the systemic circulation. For oral drugs it is the product of the fraction absorbed across the gut, the fraction surviving metabolism in the gut wall, and the fraction surviving first-pass metabolism in the liver before reaching the general circulation. First-pass (presystemic) metabolism is the loss of drug during this initial passage, and it is a major reason why some drugs have low or variable oral bioavailability.

Definition

Bioavailability is the fraction (F) of an administered dose of unchanged drug that reaches the systemic circulation; for oral administration it is the product of the fractions absorbed and surviving gut-wall and hepatic first-pass metabolism, with intravenous administration defined as 100% available.

Scope

This topic covers the definition and components of bioavailability, the concept of absolute versus relative bioavailability, and the first-pass effect by which drug is eliminated before reaching the systemic circulation. It is framed as a pharmacokinetic and physicochemical topic and does not give dosing or bioequivalence advice for specific products.

Core questions

What fraction of an administered dose reaches the systemic circulation, and why?
How does first-pass metabolism reduce oral bioavailability?
How are absolute and relative bioavailability distinguished?

Key concepts

Absolute bioavailability (F)
Relative bioavailability
Fraction absorbed
Gut-wall (intestinal) metabolism
Hepatic first-pass metabolism
Hepatic extraction ratio
Portal circulation routing
Area under the curve (AUC) as exposure measure

Mechanisms

An orally administered drug is absorbed across the intestinal epithelium, but before it reaches the systemic circulation it must traverse the gut wall and then the liver via the portal vein. Drug can be metabolised by enzymes in the intestinal wall and, crucially, extracted by the liver during this first pass; only the surviving fraction enters the general circulation. Bioavailability therefore reflects the chain of fraction absorbed, fraction escaping gut metabolism, and fraction escaping hepatic extraction. Drugs with a high hepatic extraction ratio undergo extensive first-pass loss and have low, often variable, oral bioavailability, whereas routes that bypass the portal circulation avoid hepatic first pass. Bioavailability is quantified by comparing systemic exposure (area under the concentration-time curve) after oral and intravenous doses; for absorption-limited compounds, solubility and permeability set an upper bound on the fraction absorbed (Amidon, 1995; Rowland & Tozer, 2011). Across many drugs, the determinants of clearance that drive hepatic extraction are correspondingly reflected in observed bioavailability (Obach, 2008).

Clinical relevance

Bioavailability and first-pass metabolism explain why the same drug can require different doses by different routes and why some drugs are unsuitable for oral use. The concept also underlies bioequivalence, the comparison of systemic exposure between products. This entry describes these concepts at a reference level and is not a basis for individual dosing, route selection, or product substitution decisions.

Evidence & guidelines

Bioavailability and bioequivalence are assessed through systemic exposure comparisons and are the subject of regulatory guidance; the Biopharmaceutics Classification System supports biowaivers in which in vitro dissolution can substitute for in vivo bioequivalence studies for qualifying drugs (Amidon, 1995). Pharmacokinetic compendia relate observed bioavailability to extraction and clearance properties (Obach, 2008; Rowland & Tozer, 2011).

History

The first-pass effect was recognised in the mid-twentieth century as drugs were observed to be much less effective orally than parenterally, attributable to presystemic hepatic extraction. Bioavailability was formalised as a quantitative fraction within pharmacokinetics, and the Biopharmaceutics Classification System (1995) later connected the absorption component to solubility and permeability, framing the regulatory treatment of bioequivalence and biowaivers.

Key figures

Gordon Amidon
Hans Lennernas
Malcolm Rowland
Thomas Tozer
R. Scott Obach

Seminal works

amidon-1995
obach-2008

Frequently asked questions

What does bioavailability mean?: Bioavailability is the proportion of an administered dose of unchanged drug that reaches the systemic circulation. By definition an intravenous dose is fully available (100%), and other routes are compared against it.
Why does first-pass metabolism lower oral bioavailability?: After oral absorption, drug passes through the gut wall and liver before entering the general circulation. Enzymes there can metabolise a substantial fraction during this first pass, so less unchanged drug reaches the systemic circulation.