Bioavailability and Metabolism

Bioavailability is the fraction of an administered dose that reaches the systemic circulation in an active form, and metabolism is the set of enzymatic transformations that compounds undergo in the body. For natural products the two are tightly linked: extensive metabolism in the gut wall and liver is a major reason why many plant constituents have low and variable bioavailability.

Definition

Bioavailability is the rate and extent to which the active moiety of a compound reaches the systemic circulation; metabolism is its enzymatic conversion, principally through phase I (oxidation, reduction, hydrolysis) and phase II (conjugation) reactions, that influences both its exposure and its activity.

Scope

This entry covers the determinants of bioavailability and the metabolic biotransformation of natural products, including first-pass metabolism, phase I and phase II reactions, the physicochemical properties that govern absorption, and the resulting low exposure of compounds such as curcumin and many polyphenols. It is conceptual and methodological and provides no dosing or therapeutic recommendations.

Core questions

• What determines how much of an ingested natural product reaches the bloodstream in active form?
• How do phase I and phase II metabolism transform plant constituents?
• Which physicochemical properties favour or limit oral absorption?
• Why do compounds such as curcumin and many polyphenols show low bioavailability despite activity in vitro?

Key concepts

• Oral bioavailability and the fraction absorbed
• First-pass (presystemic) metabolism
• Phase I metabolism (oxidation, reduction, hydrolysis)
• Phase II metabolism (glucuronidation, sulfation, methylation)
• Solubility and permeability as absorption determinants
• Drug-likeness and the rule of five
• Active versus inactive metabolites

Mechanisms

After absorption, a compound passes through the gut wall and liver before reaching the systemic circulation, where presystemic (first-pass) metabolism can remove much of the dose. Phase I reactions modify the molecule (for example by oxidation), and phase II reactions conjugate it to make it more water-soluble for excretion; for polyphenols, conjugation is so extensive that circulating forms are largely metabolites and exposure is low (Manach et al., 2004; Manach et al., 2005). Curcumin exemplifies poor bioavailability driven by limited absorption together with rapid metabolism and elimination (Anand et al., 2007). Whether a compound is absorbed at all is shaped by physicochemical properties such as solubility and permeability, summarized in drug-likeness rules for oral absorption (Lipinski et al., 2001).

Clinical relevance

Bioavailability and metabolism explain the frequent gap between a natural product's activity in laboratory assays and its measurable systemic exposure, which is central to interpreting efficacy claims and anticipating interactions. This entry describes those principles for reference and is not a source of dosing or individualized treatment advice.

History

As pharmacokinetic concepts of bioavailability and metabolism were formalized in twentieth-century pharmacology, they were progressively applied to natural products. Reviews of polyphenol bioavailability established that dietary and herbal phenolics are heavily metabolized and poorly available (Manach et al., 2004; Manach et al., 2005), studies of curcumin made low bioavailability a recurring theme (Anand et al., 2007), and drug-likeness rules linked physicochemical properties to oral absorption (Lipinski et al., 2001).

Key figures

• Claudine Manach
• Bharat B. Aggarwal
• Christopher A. Lipinski
• Augustin Scalbert

Seminal works

• manach-2004
• manach-2005
• anand-2007
• lipinski-2001

Frequently asked questions

What is bioavailability?

It is the fraction of an administered dose that reaches the systemic circulation in active form. A compound active in a test tube may have low bioavailability if little of it survives absorption and first-pass metabolism.

How does metabolism reduce the bioavailability of natural products?

Enzymes in the gut wall and liver transform many plant constituents before they reach the bloodstream, often converting them into conjugated or otherwise modified metabolites, so the parent compound's exposure is low.