Metabolism and Biotransformation

Drug metabolism, or biotransformation, is the enzymatic conversion of a drug into other chemical species — usually more water-soluble metabolites that are more readily excreted. It is conventionally divided into Phase I reactions, which introduce or expose functional groups, and Phase II reactions, which conjugate the drug or its Phase I product to an endogenous molecule.

Definition

Biotransformation is the enzyme-catalysed chemical modification of a drug within the body, typically converting lipophilic compounds into more polar metabolites that can be eliminated; it encompasses Phase I (oxidation, reduction, hydrolysis) and Phase II (conjugation) reactions.

Scope

This topic covers the enzymatic transformation of drugs, the Phase I and Phase II reaction families, the central role of the cytochrome P450 system in hepatic metabolism, and the consequences of metabolism for clearance and drug interactions. It treats metabolism as a determinant of disposition; it is educational and gives no individualised dosing advice.

Core questions

• Which enzyme systems carry out the major Phase I and Phase II reactions?
• How does cytochrome P450 activity govern the metabolic clearance of many drugs?
• Why does metabolism usually increase a compound's water solubility and aid excretion?
• How do enzyme induction and inhibition produce clinically relevant drug interactions?

Key concepts

• Phase I reactions (oxidation, reduction, hydrolysis)
• Phase II reactions (conjugation)
• Cytochrome P450 (CYP) enzyme system
• Hepatic metabolism and the first-pass effect
• Enzyme induction and inhibition
• Active and reactive metabolites
• Prodrug activation
• Metabolic drug-drug interactions

Mechanisms

Most drug metabolism is catalysed by hepatic enzymes. Phase I reactions — predominantly oxidations carried out by the cytochrome P450 superfamily — introduce or unmask polar functional groups, while Phase II reactions conjugate the drug or its metabolite to groups such as glucuronic acid or sulphate, further increasing water solubility for excretion (Guengerich, 2001). The capacity of these enzymes, together with hepatic blood flow, sets the hepatic clearance of a drug: for high-extraction drugs clearance is flow-limited, whereas for low-extraction drugs it is governed by enzyme activity and protein binding (Wilkinson & Shand, 1975). Because P450 enzymes can be induced or inhibited by co-administered compounds, metabolism is a principal site of drug-drug interactions, and in vitro data are used to anticipate such interactions in advance (Wienkers & Heath, 2005). Metabolism is not always inactivating: some metabolites are pharmacologically active, and prodrugs depend on metabolism for activation.

Clinical relevance

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 interaction and variability; it does not provide dosing or interaction-management instructions for any patient.

Evidence & guidelines

Regulatory guidance on drug-drug interaction evaluation is built on the cytochrome P450 framework and on the principle of projecting in vivo interactions from in vitro enzyme data (Wienkers & Heath, 2005). The reaction chemistry and the physiological model of hepatic clearance are documented in comprehensive reviews (Guengerich, 2001; Wilkinson & Shand, 1975) and standard texts (Rowland & Tozer, 2011).

History

The cytochrome P450 system was identified as the engine of oxidative drug metabolism in the second half of the twentieth century, and the physiological model relating hepatic clearance to organ blood flow and intrinsic enzymatic activity was articulated in 1975 (Wilkinson & Shand). Subsequent characterisation of the diversity of P450 reactions (Guengerich, 2001) and of in vitro–in vivo interaction prediction (Wienkers & Heath, 2005) extended the field toward routine prospective assessment of metabolic interactions.

Key figures

• F. Peter Guengerich
• Grant R. Wilkinson
• Larry C. Wienkers

Seminal works

• guengerich-2001
• wilkinson-shand-1975
• wienkers-heath-2005

Frequently asked questions

What is the difference between Phase I and Phase II metabolism?

Phase I reactions (oxidation, reduction, hydrolysis) introduce or expose a reactive functional group, often via cytochrome P450 enzymes. Phase II reactions conjugate the drug or its Phase I product to an endogenous molecule, generally producing a more water-soluble compound that is easier to excrete.

Why is the cytochrome P450 system so important in drug metabolism?

The cytochrome P450 superfamily catalyses the majority of oxidative Phase I reactions for clinically used drugs. Because these enzymes can be induced or inhibited by other compounds, they are a major source of metabolic drug-drug interactions and of between-individual variability in drug exposure.