Metabolism and Biotransformation
Metabolism, or biotransformation, is the metabolic (M) component of pharmacokinetics: the enzymatic conversion of a drug into other chemical species, usually more water-soluble metabolites that can be eliminated. As an area within pharmacokinetics it organises the reaction families, enzyme systems, and sources of variability that determine how quickly the body clears a drug.
Definition
Biotransformation is the enzyme-catalysed chemical modification of a drug within the body, conventionally divided into Phase I reactions (oxidation, reduction, hydrolysis) that introduce or expose functional groups and Phase II reactions (conjugation) that attach an endogenous molecule, together generally producing more polar metabolites for excretion.
Scope
This area provides an orienting overview of drug biotransformation as a determinant of clearance and exposure, and points to its constituent topics: Phase I and Phase II reactions, the cytochrome P450 enzyme system, and genetic variation in metabolising enzymes. It is educational and gives no individualised dosing advice.
Sub-topics
Core questions
- How does biotransformation convert lipophilic drugs into excretable metabolites?
- How do Phase I and Phase II reactions relate to one another?
- Why is metabolic capacity a principal source of variability in drug exposure between individuals?
- How do enzyme induction, inhibition, and genetic variation alter metabolic clearance?
Key concepts
- Phase I reactions (oxidation, reduction, hydrolysis)
- Phase II reactions (conjugation)
- Cytochrome P450 (CYP) enzyme system
- Metabolic clearance and the first-pass effect
- Enzyme induction and inhibition
- Active and reactive metabolites; prodrug activation
- Genetic polymorphism of metabolising enzymes
Mechanisms
Most drug metabolism is catalysed by hepatic enzymes acting in two broad steps. Phase I reactions, dominated by the cytochrome P450 superfamily, introduce or unmask polar functional groups; Phase II reactions conjugate the drug or its Phase I product to an endogenous group such as glucuronic acid or sulphate, generally raising water solubility for excretion (Guengerich, 2007). The capacity and activity of these enzymes set the metabolic clearance of a drug and, through induction, inhibition, and inherited differences in enzyme activity, account for much of the between-individual variability in drug response (Wilkinson, 2005). Metabolism is not always inactivating: some metabolites are pharmacologically active, and prodrugs depend on metabolism for their conversion to the active species.
Clinical relevance
Differences in metabolic capacity, enzyme induction and inhibition, and genetic variation in metabolising enzymes explain much of the variability in drug exposure between individuals and underlie many drug-drug interactions. This entry describes those mechanisms as background for understanding variability; it does not provide dosing or interaction-management instructions for any patient.
Evidence & guidelines
The chemistry of biotransformation and its role in chemical toxicity are documented in comprehensive reviews (Guengerich, 2007), and the link between metabolism and between-patient variability in drug response is summarised in major clinical reviews (Wilkinson, 2005) and standard texts (Rowland & Tozer, 2011). Detailed enzyme-level and guideline material is covered in the constituent topics.
History
The cytochrome P450 system was identified as the engine of oxidative drug metabolism in the second half of the twentieth century, and the two-phase scheme of biotransformation became the organising framework for understanding how the body disposes of foreign compounds. Recognition that metabolic capacity is a principal driver of variability in drug response (Wilkinson, 2005) helped place metabolism at the centre of clinical pharmacokinetics.
Key figures
- F. Peter Guengerich
- Grant R. Wilkinson
Related topics
Seminal works
- wilkinson-2005
- guengerich-2007
Frequently asked questions
- What does biotransformation accomplish for the body?
- It chemically modifies drugs, usually converting lipophilic compounds into more water-soluble metabolites that the kidneys and bile can eliminate, thereby helping to terminate drug action and clear foreign compounds.
- Why is metabolism a major source of variability in drug response?
- Metabolic enzymes differ in activity between individuals because of genetic variation, and their activity can be raised or lowered by other drugs, so the same dose can produce very different exposures depending on a person's metabolic capacity.